2-saccharinylmethyl aryl carboxylate

ABSTRACT

4-R 4  -R 5  -2-Saccharinylmethyl aryl carboxylates, useful in the treatment of degenerative diseases, are prepared by reacting a 4-R 4  -R 5  -2-halomethylsaccharin with an arylcarboxylic acid in the presence of an acid-acceptor.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a division of our prior copending application Ser.No. 07/782,016, filed Oct. 24, 1991 now U.S. Pat. No. 5,128,339 which inturn is a continuation-in-part of our prior copending application Ser.No. 07/608068, filed Nov. 1, 1990 now abandoned.

BACKGROUND OF THE INVENTION

(a) Field of the Invention

This invention relates to novel 2-saccharinylmethylaryl carboxylates,which inhibit the enzymatic activity of proteolytic enzymes, tocompositions containing the same, to the method of use thereof in thetreatment of degenerative diseases and to processes for theirpreparation.

(b) Information Disclosure Statement

The inhibition of proteolytic enzymes by nontoxic reagents is useful inthe treatment of degenerative disorders, such as emphysema, rheumatoidarthritis and pancreatitis, in which proteolysis is a substantiveelement.

Protease inhibitors are widely utilized in biomedical research. Serineproteases are the most widely distributed class of proteolytic enzymes.Some serine proteases are characterized as chymotrypsin-like orelastase-like based upon their substrate specificity.

Chymotrypsin and chymotrypsin-like enzymes normally cleave peptide bondsin proteins at a site at which the amino acid residue on the carboxylside is typically Trp, Tyr, Phe, Met, Leu or another amino acid residuewhich contains aromatic or large alkyl side chains.

Elastase and elastase-like enzymes normally cleave, peptide bonds at asite at which the amino acid residue on the carboxyl side of the bond istypically Ala, Val, Ser, Leu or other similar, smaller amino acids.

Both chymotrypsin-like and elastase-like enzymes are found inleukocytes, mast cells and pancreatic juice in higher organisms, and aresecreted by many types of bacteria, yeast and parasites.

Japanese Patent Publication 7200419, published Jan. 7, 1972, discloses anumber of 2-saccharinylmethylbenzoates, including 2-saccharinylmethylbenzoate per se and 2-saccharinylmethyl 2,4-dichlorobenzoate and4-nitrobenzoate. The compounds are said to "have strong activity againstrice blast, rice sheath blight, rice helminthosporium leaf spot and ricebacterial leaf blight disease".

Sunkel et al., J. Med. Chem., U, 31, 1886-1890 (1988) disclose a seriesof 2-saccharinyl-lower-alkyl-1,4-dihydropyridine-3-carboxylates havingplatelet aggregation inhibitory and anti-thrombotic activities.

Chen U.S. Pat. No. 4,263,393, patented Apr. 21, 1981, discloses various2-aroylmethylsaccharins useful as "photographic elements and filmunits".

Mulvey et al. U.S. Pat. No. 4,195,023, patented Mar. 25, 1980, disclosesR₁ -2-R₂ CO-1,2-benzisothiazol-3-ones, where R₁ is halogen, alkoxy,alkylamino, dialkylamino, alkoxycarbonyl, amino, nitro or hydrogen inthe benzenoid ring and R₂ is hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, halophenyl, heteroaryl or substituted heteroaryl, and R₁-2-A-CO saccharins, where R₁ has the same meanings as the benzenoid ringsubstituents in the 1,2-benzisothiazol-3-ones and A is alkyl, alkenyl,alkynyl, cycloalkyl, fluorophenyl, heteroaryl or substitutedheteroaryl.The compounds are said to have elastase inhibitory activity and to beuseful in the treatment of emphysema.

Zimmerman et al., J. Biol. Chem., 225(20), 9848-9851 (1980) discloseN-acylsaccharins, where the acyl group is furoyl, thenoyl, benzoyl,cyclopropanoyl, ethylbutyryl and acryloyl, having serine proteaseinhibitory activity.

Japanese Patent Publication 73/35457, published Oct. 27, 1973, discloses4-methylphenyl 2-saccharinylcarboxylate which is said to havebactericidal and fungicidal activities.

Several classes of compounds are known to be serine protease inhibitors.For example Powers U.S. Pat. No. 4,659,855 discloses arylsulfonylfluoride derivatives useful as elastase inhibitors. Doherty et al. U.S.Pat. Nos. 4,547,371 and 4,623,645 disclose cephalosporin sulfones andsulfoxides, respectively, which are stated to be potent elastaseinhibitors useful in the treatment of inflammatory conditions,especially arthritis and emphysema.

Teshima et al., J. Biol. Chem., ZU(9), 5085-5091 (1982) report theresults of studies on serine proteases (human leukocyte elastase,porcine pancreatic elastase, cathepsin G and bovine chymotrypsinA.sub.α) with 4-nitrophenylesters and thioesters ofN-trifluoroacetylanthranilates, 2-substituted-4H-3,1-benzoxazin-4-ones,2-substituted-4-quinazolinones and 2-substituted-4-chloroquinazolines.

Cha, Biochem. Pharmacol., 24, 2177-2185 (1975) discusses kineticapproaches to the study of the binding of inhibitors to macromolecules,such as enzymes, and methods for determination of such parameters as theinhibition constants, reaction rates and bound and unbound enzymeconcentrations.

Jones et al., U.S. Pat. No. 4,276,298 discloses2-R-1,2-benzisothiazolinone-1,1-dioxides, where R is phenyl substitutedby fluoro, dinitro, trifluoromethyl, cyano, alkoxycarbonyl,alkylcarbonyl, carboxyl, carbamoyl, alkylacylamino, alkylsulfonyl,N,N-dialkylsulfamoyl, trifluoromethoxy, trifluoromethylthio,trifluoromethylsulfonyl and trifluoromethylsulfinyl, or pyridylsubstituted the same as R when R is phenyl except that pyridyl may alsobe mononitro substituted. The compounds are said to have protease enzymeinhibitory activity, especially elastase inhibitory activity, and to beuseful in the treatment of emphysema, rheumatoid arthritis "and otherinflammatory diseases".

Powers, Biochem., 2A, 2048-2058 (1985) discloses studies of theinhibitions of four chymotrypsin-like enzymes, cathepsin G, rat mastcell proteases I and II, human skin chymase and chymotrypsin A.sub.α, byN-furoylsaccharin and N-(2,4-dicyanophenyl)saccharin.

Svoboda et al., Coll. Czech. Chem. Commun., 51, 1133-1139 (1986)disclose the preparation of4-hydroxy-2H-1,2-benzothiazine-3-carboxylates by intramolecularDieckmann condensation of2H-1,2-benzisothiazol-3-one-2-acetate-1,1-dioxide esters.

Reczek et al. U.S. Pat. Nos. 4,350,752 and 4,363,865 and Vanmeter et al.U.S. Pat. No. 4,410,618 relate to photographic reagents (Reczek U.S.Pat. No. 4,350,752 and Vanmeter et al.) and photographic dyes (ReczekU.S. Pat. No. 4,363,865) and disclose various 2-substituted-saccharinsuseful for such applications, for example "photographic reagents" boundthrough a heteroatom to an "imidomethyl blocking" group (Reczek U.S.Pat. No. 4,350,752), "carrier-diffusible photographic dyes" bound to thenitrogen atom of an imide through a 1,1-alkylene group (Reczek U.S. Pat.No. 4,363,865) and N-acylmethylimides which are described as "blockedphotographic reagents" and which have a "residue of an organicphotographic reagent containing a hetero atom through which it is boundto the blocking group" (Vanmeter).

Freed U.S. Patent 3,314,960 discloses2-(1,1,3-trioxo-1,2-benzisothiazol-2-yl)glutarimides which are stated tobe useful as sedatives.

2-Chloromethylsaccharin is disclosed in French Patent 1,451,417 as anintermediate for the preparation of N-methylsaccharind,1-trans-chrysanthemate, useful as an insecticide, and Lo U.S. Pat. No.3,002,884 discloses 2-chloro, 2-bromo and 2-iodomethylsaccharins, usefulas fungicidal agents.

SUMMARY OF THE INVENTION

In a composition of matter aspect, this invention relates to 4-R⁴ -R⁵-2-saccharinylmethyl aryl carboxylates and4,5,6,7-tetrahydro-2-saccharinylmethyl aryl carboxylates which haveprotease enzyme inhibitory activity and which are useful in thetreatment of degenerative diseases.

In a composition aspect, the invention relates to compositions for thetreatment of degenerative diseases which comprise a pharmaceuticalcarrier and an effective proteolytic enzyme inhibiting amount of a 4-R⁴-R⁵ -2-saccharinylmethyl aryl carboxylate or a4,5,6,7-tetrahydro-2-saccharinylmethyl aryl carboxylate.

In a method aspect, the invention relates to a method of use of said2-saccharinylmethyl aryl carboxylates in the treatment of degenerativediseases which comprises administering to a patient in need of suchtreatment a medicament containing an effective proteolytic enzymeinhibiting amount of a 4-R⁴ -R⁵ -2-saccharinylmethyl aryl carboxylate or4,5,6,7-tetrahydro-2-saccharinylmethyl aryl carboxylate.

In process aspects, the invention relates to processes for thepreparation of said 4-R⁴ -R⁵ -2-saccharinylmethyl aryl carboxylates and4,5,6,7-tetrahydro-2-saccharinylmethyl aryl carboxylates which comprisereacting (1) a 2-halomethylsaccharin with an aryl carboxylic acid in thepresence of an acid-acceptor, or (2) reacting a saccharin with achloromethyl ester of an aryl carboxylic acid in the presence of an acidacceptor, or (3) reacting an alkali metal or thallium salt of theappropriate acid with the appropriate halomethyl species.

In a further process aspect, the invention relates to a process for thepreparation of 4-R⁴ -R⁵ -saccharins, useful as intermediates for thepreparation of the corresponding 4-R⁴ -R⁵ -2-saccharinylmethyl arylcarboxylates, which comprises reacting a 2-R⁴ -R⁵-N,N-di-lower-alkylbenzamide with a lower-alkyl alkali metal such as aninert organic solvent; reacting the resulting alkali metal salt eitherwith sulfur dioxide followed by hydroxylamine-O-sulfonic acid in thepresence of base or with a sulfuryl halide followed by ammonia; heatingthe resulting 2-R⁴ -R⁵ -6-aminosulfonyl-N,N-di-lower-alkylbenzamide in alower-alkanoic acid; and treating the resulting 4-R⁴ -R⁵ -saccharindi-lower-alkylammonium salt with aqueous acid.

In a further process aspect, the invention relates to a process for thepreparation of 2-chloromethyl saccharins useful as intermediates for thepreparation of 2-saccharinylmethyl aryl carboxylates, which comprisesreacting a saccharin with a chlorosilane and formaldehyde in thepresence of a Lewis acid.

In a further process aspect, the invention relates to a process forpreparing 4-n-lower-alkylsaccharins, useful as intermediates, whichcomprises protecting the benzylic position of a2-n-lower-alkyl-N,N-dialkylbenzamide with an appropriate trialkylsilane,constructing the isothiazole ring as above, and deprotecting using asource of fluoride anion.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

More specifically this invention relates to 4-R⁴ -R⁵-2-saccharinylmethyl aryl carboxylates having the formula: ##STR1##wherein: Ar is phenyl, naphthyl or anthryl or such groups substituted byfrom one to three, the same or different, members of the groupconsisting of lower-alkyl, perfluorolower-alkyl, perchlorolower-alkyl,lower-alkoxy, halogen, nitro, cyano, carboxy, PO(lower-alkoxy)₂, amino,lower-alkylamino, dilower-alkylamino, lower-alkanoylamino,lower-alkoxycarbonyl, hydroxy, benzyloxy, carboxylower-alkoxy, --SO₂--N═B, --CO--N═B, --(alkylene)--N═B, --COO(alkylene)--N═B,--NH(alkylene)--N═B; --N(lower-alkyl)--(alkylene)--N═B, or--O--(alkylene)--N═B, where N═B in each instance is amino,lower-alkylamino, di-lower-alkyl-amino, 1-azetidinyl, 1-pyrrolidinyl,1-piperidinyl, 4-morpholinyl, 1-piperazinyl,4-lower-alkyl-1-piperazinyl, 4-benzyl-1-piperazinyl, 1-imidazolyl,carboxy-lower-alkylamino; or --NR--(alkylene)--N(alkyl)2, where Rlower-alkyl

R⁴ is hydrogen, halogen, lower-alkyl, perfluorolower-alkyl,perchlorolower-alkyl, lower-alkenyl, lower-alkynyl, cyano, amino,lower-alkylamino, dilower-alkylamino, lower-alkoxy, benzyloxy,lower-alkoxycarbonyl, phenyl or carboxamido; and

R⁵ is hydrogen or from one to two the same or different substituents inany of the 5-, 6- or 7-positions selected from halogen, cyano, nitro,N═B, 1-lower-alkyl-2-pyrrolyl, lower-alkylsulfonylamino,polyfluoroloweralkylsulfonylamino, polychlorolower-alkylsulfonylamino,aminosulfonyl, lower-alkyl, polyfluorolower-alkyl,polychlorolower-alkyl, cycloalkyl, lower-alkoxy, hydroxy, carboxy,carboxamido, hydroxylower-alkyl, methylenedioxy, cycloalkyloxy, formyl,aminomethyl, lower-alkylsulfonyl, polyfluorolower-alkylsulfonyl,polychlorolower-alkylsulfonyl, lower-alkylsulfonylaminosulfonyl,di(loweralkyl)phosphonoxy, lower-alkoxypoly-loweralkyleneoxy,hydroxylower-alkoxy, polyhydroxylower-alkoxy, or acetal or ketalthereof, poly(lower-alkoxy)lower-alkoxy, --O--(alkylene)--COOR,--O--(alkylene)--N═B, --SR, --SOR, --SO₂ R or --OCOR, where R islower-alkyl, phenyl, benzyl or naphthyl, or phenyl or naphthylsubstituted by from one to two substituents selected from lower-alkyl,lower-alkoxy or halogen, and --N═B has the meanings given above,

or R⁵ is a 5- or 6-membered saturated ring fused to the saccharin at the5,6 or 6,7-positions, said ring containing two heteroatoms chosen fromthe group consisting of nitrogen, oxygen and sulfur, or a methylatedderivative of said ring;

or acid-addition salts of basic saccharinylmethyl carboxylates orbase-addition salts of acidic saccharinylmethylcarboxylates, with theproviso that, when R⁴ and R⁵ are both hydrogen, Ar cannot be eitherphenyl, 2,4-dichlorophenyl or 4-nitrophenyl.

Preferred compounds of formula I above are those wherein:

Ar is phenyl, naphthyl or anthryl or such groups substituted by from oneto three, the same or different, members of the group consisting oflower-alkyl, perfluorolower-alkyl, lower-alkoxy, halogen, nitro,PO(lower-alkoxy)2, lower-alkanoylamino, hydroxy, carboxylower-alkoxy,benzyloxy, --SO₂ --N═B or --O--(alkylene)-N═B, where N═B isdi-lower-alkylamino, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl,1-piperazinyl, 4-lower-alkyl-l-piperazinyl, 4-benzyl-1-piperazinyl,carboxylower-alkylamino or --NR-- (alkylene)-N(alkyl)₂, where R islower-alkyl;

R⁴ is hydrogen, primary or secondary-lower-alkyl, lower-alkoxy orphenyl; and

R⁵ is hydrogen, hydroxy, lower-alkoxy, methylenedioxy, cycloalkyloxy,hydroxylower-alkoxy, polyhydroxylower-alkoxy, or acetal or ketalthereof, poly(lower-alkoxy)lower-alkoxy, --O--(alkylene)--COOR, orO--(alkylene)-N═B or R⁵ is a [6,5-fused 1,3-oxazine.

Particularly preferred compounds of formula I are those wherein:

Ar is phenyl or phenyl substituted by from one to three, the same ordifferent, members selected from the group consisting of lower-alkyl,lower-alkoxy, halogen, hydroxy, carboxylower-alkoxy, benzyloxy, --SO₂--N═B or --O-- (alkylene)--N═B, where N═B is dilower-alkylamino,1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 1-piperazinyl,4-lower-alkyl-1-piperazinyl, 4-benzyl-1-piperazinyl,carboxylower-alkylamino or --NR--(alkylene)-N(alkyl)₂, where R islower-alkyl;

R⁴ is primary or secondary lower-alkyl or lower-alkoxy; and

R⁵ is hydrogen, lower-alkoxy, methylenedioxy, cycloalkyloxy,hydroxylower-alkoxy, polyhydroxylower-alkoxy, or acetal or ketalthereof, poly(lower-alkoxy)lower-alkoxy, --O--(alkylene)--COOR, orO--(alkylene)--N═B.

Other preferred compounds of formula I are those wherein:

Ar is phenyl, naphthyl or anthryl, or phenyl substituted by from one tothree, the same or different, members selected from the group consistingof lower-alkyl, perfluoro-lower-alkyl, lower-alkoxy, halogen orlower-alkanoylamino;

R⁴ is hydrogen, primary or secondary lower-alkyl, lower-alkoxy orphenyl; and

R⁵ is hydrogen or lower-alkoxy.

Still other preferred compounds of formula I are these wherein:

Ar is phenyl or phenyl substituted by from one to three, the same ordifferent, members selected from the group consisting of lower-alkoxy,halogen or lower-alkyl;

R⁴ is hydrogen, primary or secondary-lower-alkyl or lower-alkoxy; and

R⁵ is hydroxy in any of the 5-, 6- or 7-positions.

It should be understood that the compounds having the general structuralformula I are usually named in the chemical literature as1,2-benzisothiazol-3(2H)-one 1,1-dioxides. However for the sake ofbrevity, such compounds are frequently named as saccharin derivatives,and that nomenclature will be used hereinafter in describing thecompounds of the invention and their biological properties.

The invention also relates to 4,5,6,7-tetrahydro2-saccharinylmethyl arylcarboxylates of formula VI ##STR2## wherein R^(4a) is hydrogen,lower-alkyl or phenyl, R⁶ is hydrogen or primary lower-alkyl or R^(4a)and R⁶ together form a spirocyclopropyl ring, R⁷ is hydrogen orlower-alkoxy, and Ar is as defined for formula I.

Preferred tetrahydrosaccharins of formula VI are those wherein R^(4a) ishydrogen, methyl, ethyl or isopropyl, R⁶ is hydrogen or methyl, R7 ishydrogen or methoxy and Ar is phenyl substituted by from one to three,the same or different, members of the group consisting of lower-alkyl,lower-alkoxy, halogen, hydroxy and --O--(alkylene)--N═B.

The invention also relates to compounds of the formula ##STR3## whereinA is methylene, ethylene or dimethylmethylene and Ar is phenyl, naphthylor anthryl or such groups substituted by from one to three, the same ordifferent, members of the group consisting of lower-alkyl,perfluorolower-alkyl, perchlorolower-alkyl, lower-alkoxy, halogen,nitro, cyan, carboxy, OPO(lower-alkoxy)₂, amino, lower-alkylamino,dilower-alkylamino, lower-alkanoylamino, lower-alkoxycarbonyl, hydroxy,benzyloxy, carboxylower-alkoxy, --SO₂ --N═B, --CO--N═B,--(alkylene)--N═B, --COO(alkylene)--N═B, --NH(alkylene)N═B;--N(lower-alkyl)--(alkylene)--N═B; or --O--(alkylene)--N═B, where N═B ineach instance is amino, lower-alkylamino, dilower-alkyl-amino,1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl,1-piperazinyl, 4-lower-alkyl-1-piperazinyl, 4-benzyl-l-piperazinyl,1-imidazolyl or carboxy-lower-alkylamino.

As used herein the terms lower-alkyl, lower-alkoxy and lower-alkane meanmonovalent aliphatic radicals, including branched chain radicals, offrom one to ten carbon atoms. Thus the lower-alkyl (or lower-alkane)moiety of such groups include, for example, methyl, ethyl, propyl,isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, 2-methyl-3-butyl,1-methylbutyl, 2-methylbutyl, neopentyl, n-hexyl, 1-methylpentyl,3-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 2-hexyl, 3-hexyl,1,1,3,3-tetramethylpentyl, 1,1-dimethyloctyl and the like.

As used herein the term halogen (or halo) means fluorine, chlorine,bromine or iodine.

As used herein the terms lower-alkenyl and lower-alkynyl meanmonovalent, unsaturated radicals, including branched chain radicals, offrom two to ten carbon atoms and thus include 1-ethenyl, 1-(2-propenyl),1-(2-butenyl), 1-(1-methyl-2-propenyl), 1-(4-methyl-2-pentenyl),4,4,6-trimethyl-2-heptenyl, 1-ethynyl, 1-(2-propynyl), 1-(2-butynyl),1-(1-methyl-2-propynyl), 1-(4-methyl-2-pentynyl), and the like.

As used herein, the term alkylene means divalent, saturated radicals,including branched chain radicals, of from two to ten carbon atoms andhaving their free valences on different carbon atoms and thus includes1,2-ethylene, 1,3-propylene, 1,4-butylene, 1-methyl-1,2-ethylene,1,8-octylene and the like.

As used herein cycloalkyl means C₃ through C₇ saturated monocyclichydrocarbon residues and thus includes cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl.

The compounds of the present invention inhibit the activity of serineproteases, specifically human leukocyte elastase and thechymotrypsin-like enzymes, and are thus useful in the treatment ofdegenerative disease conditions such as emphysema, rheumatoid arthritis,pancreatitis, cystic fibrosis, chronic bronchitis, adult respiratorydistress syndrome, inflammatory bowel disease, psoriasis, bullouspemphigoid and alpha-1-antitrypsin deficiency.

The compounds of formula I and formula VI are prepared by reaction of a2-halomethylsaccharin or 2-halomethyl-4,5,6,7-tetrahydrosaccharin withan appropriate aryl carboxylic acid, Ar--COOH or by reaction of asaccharin or tetrahydrosaccharin with a chloromethyl ester of an arylcarboxylic acid. ##STR4## The reaction can either be carried out in thepresence of an acid-acceptor, such as an alkali metal carbonate, atrilower-alkylamine or 1,8-diazabicyclo-[5.4.0.]undec-7-ene, hereinafterDBU. Alternatively the salt of an alkali metal or thallous salt of thearyl carboxylic acid can be used (prepared by reaction of the acid withan alkali metal carbonate or thallous lower-alkoxide). The reaction iscarried out in an organic solvent inert under the conditions of thereaction, for example acetone, methyl ethyl ketone (MEK), acetonitrile,tetrahydrofuran (THF), diethyl ether, dimethylformamide (DMF),N-methylpyrrolidinone, methylene dichloride (MDC), xylene, toluene orlower-alkanols, at a temperature in the range from ambient up to theboiling point of the solvent used.

The 4-R⁴ -R⁵ -2-halomethylsaccharins required for the preparation of thecompounds of formula I are prepared by the methods described by D'Alelioet al., J. Macromol. Sci-Chem., A3(5), 941 (1969) and Saari et al., J.Het. Chem., 23, 1253 (1986) ##STR5## In the method described by Saari, amethyl ester of an appropriate anthranilic acid is prepared byconventional means from the substituted anthranilic acid and the esterdiazotized. The diazonium salt is then reacted with sulfur dioxide andcupric chloride to produce a sulfonyl chloride which is then reactedwith concentrated ammonium hydroxide to produce the substitutedsaccharin derivatives of formula II. The latter, on reaction withformaldehyde in a lower-alkanol solvent, affords the 4-R⁴ -R⁵-2-hydroxymethylsaccharins of formula III, which, on reaction with athionyl halide or a phosphorus trihalide, afford the corresponding 4-R⁴-R⁵ -2-halomethylsaccharin derivatives of formula IV.

The 4-R⁴ -R⁵ -2-halomethylsaccharins of formula IV, where X is chlorineor bromine, can also be prepared by reaction of a corresponding 4-R⁴ -R⁵-2-phenylthiomethylsaccharin with a sulfuryl halide in an inert organicsolvent, for example MDC, ethylene dichloride (EDC) or carbontetrachloride, at a temperature from around 0° C. to around 30° C. The4-R⁴ -R⁵ -2-phenylthiomethylsaccharins are in turn prepared by reactionof a 4-R⁴ -R⁵ -saccharin of formula II with a halomethylphenyl sulfidein an inert organic solvent, such as toluene, xylene, DMF or MDC at atemperature in the range from ambient up to the boiling point of thesolvent used. The reaction can be carried out by reaction of thehalomethyl phenyl sulfide with either the thallium salt of the saccharinderivative of formula II (prepared by reaction of the saccharinderivative with a thallium lower-alkoxide in a lower-alkanol); or with adilower-alkyl ammonium salt of the saccharin derivatives (prepared asdescribed below) in the presence of a tetralower-alkyl ammonium halide,such as tetrabutyl ammonium bromide (hereinafter TBAB); or with thesaccharin derivative of formula II per se in the presence of atetralower-alkyl ammonium halide; or with the saccharin derivative offormula II per se in the presence of a tetralower-alkyl ammonium halideand an alkali metal lower-alkoxide, such as potassium t-butoxide.

The saccharins of formula II may also be converted to the chloromethylsaccharins of formula IV, wherein X is C1, in one step by reaction withan excess of formaldehyde or a formaldehyde equivalent, such asparaformaldehyde or 1,3,5-trioxane, and a chlorosilane, preferablychlorotrimethylsilane in the presence of a Lewis acid, preferably acatalytic amount of stannic chloride in an inert solvent, preferably1,2-dichloroethane (ethylene dichloride, EDC).

It will be appreciated that all of the conversions of the saccharins IIto the 2-chloromethyl saccharins IV are equally applicable to theconversion of tetrahydrosaccharins VII to 2-chloromethyltetrahydrosaccharins VIII.

The compounds of formula II can also be prepared by reaction of a 2-R⁴-R⁵ -N,N-di-lower-alkylbenzamide of formula V with one molar equivalentof a lower-alkylalkalimetal, such as lithium, optionally in the presenceof a tetraloweralkylethylenediamine, in an inert organic solvent, forexample THF, and reaction of the resulting alkali metal salt either withsulfur dioxide at a temperature in the range from -50° C. to -80° C.followed by reaction of the resulting alkali metal sulfinate withhydroxylamine-O-sulfonic acid in the presence of base, or with asulfuryl halide followed by ammonia. When the sulfurdioxide-hydroxylamine-O-sulfonic acid route is used, it is particularlyadvantageous to neutralize the hydroxylamine-O-sulfonic acid with oneequivalent of sodium hydroxide prior to addition of the alkali metalsulfinate. The resulting 2-R⁴ -R⁵-6-aminosulfonylN,N-dilower-alkylbenzamide is thereafter heated in anacid medium to effect cyclization of the latter to produce thedilower-alkyl ammonium salt of the desired 4-R⁴ -R⁵ -saccharin offormula II, which can be used as such in the subsequent reaction or, ifdesired, can be hydrolyzed in dilute acid and the free saccharinisolated. It is preferred to carry out the cyclization in refluxingglacial acetic acid. The method is illustrated as follows where R⁴, R⁵and Alk have the meanings given above and the alkali metal is lithium.##STR6##

The compounds of formula II where R⁴ is either primary or secondarylower-alkyl, and which are useful as intermediates for the preparationof the compounds of formula I as described above, are prepared by one oftwo methods. The compounds of formula II where R⁴ is primary lower-alkylare prepared by reacting a 4-methyl-R⁵ -saccharin (formula II, R⁴ isCH₃) with two molar equivalents of a lower-alkyl lithium in an inertorganic solvent, for example THF, and reacting the resulting lithiumsalt with one molar equivalent of a lower-alkyl halide, both reactionsbeing carried out at a temperature in the range from about -50° C. to-80° C.

Another method for preparing the compounds of formula II where R⁴ iseither primary or secondary lower-alkyl comprises reaction of a2-primary-lower-alkyl-R⁵ -N,N-di-lower-alkylbenzamide (formula V, R⁴ isprimary-lower-alkyl) with one molar equivalent of a lower-alkyl lithiumor a lithium dilower-alkylamide, optionally in the presence of atetralower-alkylethylenediamine, in an inert organic solvent, forexample THF, and reaction of the resulting lithium salt with one molarequivalent of a lower-alkyl halide at a temperature in the range fromabout -50° C. to -80° C. The resulting 2-primary orsecondary-lower-alkyl-R⁵ -N,N-di-lower-alkyl-benzamide is thereafterconverted to the compounds of formula 11, where R⁴ is primary orsecondary lower-alkyl, by the same sequence of reactions describedabove, i.e. by reaction of the 2-primary or secondary-lower-alkyl-R⁵-N,N-di-lower-alkylbenzamide with one molar equivalent of a lower-alkylalkali metal, such as lithium; reaction of the resulting alkali metalsalt either with sulfur dioxide followed by hydroxylamine-O-sulfonicacid in the presence of base or with a sulfuryl halide followed byammonia; and cyclization of the product to the desired 4-primary orsecondary-lower-alkyl-R⁵ -saccharin of formula II. When the2-lower-alkyl group in the 2-lower-alkyl-R⁵-N,N-di-lower-alkyl-benzamide starting material is methyl, alkylationaffords species where the 2-lower-alkyl group is either straight orbranched depending upon whether a straight or branched chainloweralkylhalide is used for the alkylation. On the other hand, when the2-lower-alkyl group in the starting material contains more than onecarbon atom, alkylation takes place on the carbon atom adjacent thebenzene ring and affords products having a sec.-lower-alkyl group at the2-position.

A particularly useful method for the preparation of compounds II whereR⁴ is n-lower-alkyl and R⁵ is hydrogen involves the protection of thebenzylic protons of the starting material V with a trialkylsilyl group,thereby permitting lithiation at the 6-position and formation of thesulfonamide as described above. ##STR7## A 2-n-lower-alkylbenzamidewherein R⁸ is lower-alkyl is silylated by forming the benzylic anionusing an alkyllithium or, preferably, a lithium dialkylamide in an inertsolvent, preferably THF, and treating with a suitablechlorotrialkylsilane, preferably chlorotrimethylsilane. The saccharin issynthesized as before, and the silyl group is removed by treatment witha source of fluoride anion, preferably cesium fluoride in DMF ortetra-n-butylammonium fluoride in an inert solvent.

Access to certain of the required intermediates in some cases requiresbuilding up the two rings making up the saccharin or tetrahydrosaccharinnucleus. Thus to prepare saccharins where R⁴ is lower-alkoxy and R⁵ is7-hydroxy, or tetrahydrosaccharins where R⁷ is lower-alkoxy, thefollowing synthesis may be used: ##STR8## 3,3-Dithiobispropionic acid isconverted to the bis acid chloride by reaction of the acid with thionylchloride, and the acid chloride is then reacted with two molarequivalents of benzylamine to produce the bis N-benzylamide. The latter,on reaction with sulfuryl chloride in an organic solvent, such as MDC,EDC or carbon tetrachloride, affords5-chloro-2-benzyl-2H-isothiazol-3-one, which is oxidized with one molarequivalent of a peracid, such as perbenzoic acid or 3-chloroperbenzoicacid, to 5-chloro-2-benzyl-2H-isothiazol-3-one-1-oxide. The latter, onheating under pressure with a 2-lower-alkoxyfuran in an organic solvent,such as benzene, toluene or xylene, affords a4-loweralkoxy-7-hydroxy-2-benzyl-1,2-benzisothiazol-2H-3-one-1-oxide.The 7-hydroxy group can, if desired, then be reacted with a lower-alkylhalide or a lower-alkoxypoly-lower-alkoxy-lower-alkyl halide to give thecorresponding 4,7-dilower-alkoxy or4-lower-alkoxy-7-lower-alkoxypoly-lower-alkoxy-2-benzyl-1,2-benzisothiazol-2H-3-one-1-oxide.Further oxidation of the product with one molar equivalent of a peracidas described above followed by catalytic debenzylation by transferhydrogenation affords the corresponding4-lower-alkoxy-7-hydroxysaccharins.

When a tetrahydrosaccharin is desired, the following modification isused: ##STR9##

The 5-chloro-2-benzyl-2H-isothiazole-3-one-1-oxide may be oxidized witha suitable oxidizing agent, preferably hydrogen peroxide in acetic acid,to the 1,1-dioxide which is then reacted under typical Diels Alderconditions with the appropriate diene and reduced to provide the2-benzyl tetrahydrosaccharin which is hydrogenolyzed as before to thetetrahydrosaccharin.

Compounds of formula II wherein R⁴ is lower-alkyl or phenyl and R₅ ishydrogen may be synthesized by an alternate route from 2-cyclohexenone:##STR10##

2-Cyclohexenone is reacted with the appropriate cuprate followed bymethyl cyanoformate according to the method of Winkler et al. [Tet.Lett. 1987, 1051 and J. Org. Chem. 54, 4491 (1989)]. The resultingβ-ketoester is reacted with benzylmercaptan in the presence of theacidic clay Montmorillonite KSF to produce a mixture of regioisomers ofthe benzylthioenol ether. The mixture is aromatized by treatment withdichlorodicyanobenzoquinone (DDQ) and oxidized with chlorine gas inaqueous acid to provide the sulfonyl chloride ester, which may then beconverted to the intermediate II as shown earlier.

The 4,5,6,7-tetrahydrosaccharins which are the starting materials forthe compounds of formula VI wherein R⁷ is hydrogen are synthesized by aroute similar to the preceding one: ##STR11##

A 3-alkyl-2-cyclohexenone is reacted with the appropriate alkyl lithiumcuprate in an ethereal solvent, preferably diethyl ether, at -50° to+20°, preferably about 0°, and the resulting adduct is treated in situwith methyl cyanoformate and hexamethylphosphoramide, The6,6-dialkyl-2-oxocyclohexane carboxylate so produced is reacted withbenzyl mercaptan as described above and the mixture of2-(benzylthio)cyclohexane carboxylates is oxidatively chlorinated asdescribed above to provide a mixture of chlorosulfonyl esters that aretreated with ammonia as before to yield the desired4,4-dialkyl-4,5,6,7-tetrahydrosaccharins.

The aryl carboxylic acids, Ar-COOH, used to prepare the final productsof formula I and VI are members of a known class and can be prepared bywell-known, conventional synthetic methods.

Chloromethyl esters of the aryl carboxylic acid may be prepared bytreating the carboxylic acid with formaldehyde or a formaldehydeequivalent, preferably paraformaldehyde, in the presence of (1) a chloroacid, preferably zinc chloride or hydrochloric acid, or (2)trimethylsilyl chloride plus stannic chloride.

Simple chemical transformations which are conventional and well known tothose skilled in the art of chemistry can be used for effecting changesin functional groups in the compounds of the invention. For example,catalytic reduction of nitro groups to produce the corresponding aminosubstituted compounds, acylation of amino-substituted species to preparethe corresponding amides, oxidation of sulfides or sulfoxides to preparethe corresponding, respective sulfoxides or sulfones, saponification ofesters to produce the corresponding carboxylic acids, catalyticdebenzylation of phenolic ethers or of benzylamines to produce thecorresponding phenols or debenzylated amines or reaction of phenols withan alkylating agent in the presence of base to produce ethers as desiredcan be carried out.

In standard biological test procedures, the compounds of formula I andVI have been found to possess human leukocyte elastase (HLE) andchymotrypsin inhibitory activities, and are thus useful in the treatmentof degenerative diseases, such as emphysema, rheumatoid arthritis,pancreatitis, cystic fibrosis, chronic bronchitis, adult respiratorydistress syndrome, inflammatory bowel disease, psoriasis, bullouspemphigoid and alpha-1-antitrypsin deficiency.

The compounds of formula I and VI having basic functions can beconverted to the acid-addition salt form by interaction of the base withan acid. In like manner, the free base can be regenerated from theacid-addition salt form in conventional manner, that is by treating thesalts with cold, weak aqueous bases, for example alkali metal carbonatesand alkali metal bicarbonates. The bases thus regenerated can beinteracted with the same or a different acid to give back the same or adifferent acid-addition salt. Thus the bases and all of theiracid-addition salts are readily interconvertible.

Likewise certain compounds of formula I and VI having acid, i.e.carboxylic acid, functions can be converted to salt forms thereof byreaction of the acid with a base, such as alkali metal or ammoniumhydroxides or with organic bases such as alkyl, dialkyl ortrialkylamines, and the acids can be regenerated from the salts bytreatment of the salts with aqueous acids.

It will thus be appreciated that formulas I and VI not only representthe structural configuration of the bases and acids, but are alsorepresentative of the structural entities which are common to all of thecompounds of formulas I and VI whether in the form of the free base, thefree acids or in the form of the salts of the bases and acids. It hasbeen found that, by virtue of these common structural entities, thecompounds of formulas I and VI and their salts have inherentpharmacological activity of a type to be more fully describedhereinbelow. This inherent pharmacological activity can be enjoyed inuseful form for pharmaceutical purposes by employing the free bases orfree acids themselves or the salts formed from pharmaceuticallyacceptable acids and bases; that is, acids or bases whose anions orcations are innocuous to the animal organism in effective doses of thesalts so that beneficial properties inherent in the common structuralentity represented by the free bases and free acids are not vitiated byside effects ascribable to the anions or cations.

In utilizing this pharmacological activity of the salt, it is preferred,of course, to use pharmaceutically acceptable salts. Although waterinsolubility, high toxicity or lack of crystalline character may makesome particular salt species unsuitable or less desirable for use assuch in a given pharmaceutical application, the water-insoluble or toxicsalts can be converted to the corresponding pharmaceutically acceptablebases by decomposition of the salts with aqueous base or aqueous acid asexplained above, or alternatively they can be converted to any desiredpharmaceutically acceptable salt by double decomposition reactionsinvolving the anion or cation, for example by ionexchange procedures.

Moreover, apart from their usefulness in pharmaceutical applications,the salts are useful as characterizing or identifying derivatives of thefree bases or free acids or in isolation or purification procedures.Like all of the salts, such characterization or purification saltderivatives can, if desired, be used to regenerate the pharmaceuticallyacceptable free bases or free acids by reaction of the salts withaqueous base or aqueous acid, or alternatively they can be converted toa pharmaceutically acceptable salt by, for example, ion-exchangeprocedures.

The novel feature of the compounds then resides in the concept of the2-saccharinylmethyl aryl carboxylates of formulas I and VI not in anyparticular acid or base moiety or acid anion or base cation associatedwith the salt forms of the compounds.

The compounds of formulas I and VI of the invention can be prepared forpharmaceutical use by incorporating them in unit dosage form as tabletsor capsules for oral administration either alone or in combination withsuitable adjuvants such as calcium carbonate, starch, lactose, talc,magnesium stearate, gum acacia and the like. Still further, thecompounds can be formulated for oral, parenteral or aerosol inhalationadministration either in aqueous solutions of water soluble salts of thecompounds or in aqueous alcohol, glycol or oil solutions or oil-wateremulsions in the same manner as conventional medicinal substances areprepared.

The percentages of active component in such compositions may be variedso that a suitable dosage is obtained. The dosage administered to aparticular patient is variable, depending upon the clinician's judgmentusing as criteria: the route of administration, the duration oftreatment, the size and physical condition of the patient, the potencyof the active component and the patient's response thereto. An effectivedosage amount of the active component can thus only be determined by theclinician after a consideration of all criteria and using his bestjudgment on the patient's behalf.

The molecular structures of the compounds of the invention were assignedon the basis of study of their infrared and NMR spectra. The structureswere confirmed by the correspondence between calculated and found valuesfor elementary analyses for the elements or by analysis of thehigh-resolution mass spectra.

The following examples will further illustrate the invention without,however, limiting it thereto. All melting points are uncorrected.

PREPARATION OF STARTING MATERIALS Preparation 1

Powdered Potassium hydroxide (7.4 g, 0.132 mol) was admixed withdimethyl sulfoxide (DMSO) (100 ml), and the mixture was stirred for 5minutes. 6-Methylanthranilic acid (10.0 g, 0.066 mol) was then added tothe mixture and iodomethane (4.52 ml, 0.073 mol) added dropwise. Thereaction mixture was stirred for 30 minutes at room temperature, thendiluted with 250 ml of ether, washed with water (3×100 ml), dried overmagnesium sulfate and concentrated. The crude product was filteredthrough a pad of flash grade (32-63) silica gel and eluted with 1:9ether:hexane to afford 4.23 g (39%) of methyl 6-methylanthranilate as anoil.

The methyl 6-methylanthranilate so prepared (4.23 g, 0.026 mol) wasdissolved in 25 ml of acetic acid and the solution cooled to 0° C.Concentrated hydrochloric acid (45 ml) was added to produce a tanslurry, A solution of 1.89 g (0.027 mol) of sodium nitrite in 8 ml waterwas added dropwise with stirring, the resulting orange solution wasstirred at 0° C. for 1 hour and then added in 6 portions to a mixture of2.18 g (0.013 mol) of cupric chloride dehydrate and sulfur dioxide (6.3g) in 33 ml of acetic acid and 6 ml of water at 0° C. The dark greensolution was stirred at room temperature overnight, poured into 300 mlof ice-water, and the solid which separated was collected and dried bysuction to provide 1.11 g of methyl 2-chlorosulfonyl-6-methylbenzoatewhich was immediately added to 100 ml of ice cold ammonium hydroxide andstirred at room temperature overnight. The solution was acidified to pH1 with concentrated hydrochloric acid, and the resulting precipitate wascollected and air-dried to provide 729 mg (12%) of 4-methylsaccharin, mp224°-2260 C.

A mixture of 1.0 g (0.005 mol) of 4-methylsaccharin, 0.33 g (0.001 mol)of TBAB and 1.2 g (0.0075 mol) of chloromethyl phenyl sulfide in 25 mlof toluene was heated under reflux for about sixteen hours and thencooled, diluted with ethyl acetate and the solution washed with aqueousbicarbonate and water. The organic layer was dried and taken to drynessto give 0.74 g of 2--phenylthiomethyl-4-methylsaccharin.

The latter (0.74 g, 0.002 mol) was dissolved in 25 ml of MDC and thesolution treated dropwise over a period of about two hours with stirringwith a solution of 0.47 g (0.003 mol) of sulfuryl chloride in MDC andthe reaction mixture taken to dryness. The yellow residual solid wastriturated with hexane and filtered and dried to give 0.46 g of2-chloro-methyl-4-methylsaccharin as a pale yellow solid.

Preparation 2

Using the procedure described above in Preparation 1, 5.0 g (0.029 mol)of 6-chloroanthranilic acid and 2.75 ml (0.044 mol) of iodomethane werereacted in the presence of 4.08 g (0.073 mol) of powdered potassiumhydroxide to give 4.22 g (78%) of methyl 6-chloroanthranilate as an oil.

4-Chlorosaccharin was prepared by the same method asused for thepreparation of 4-methylsaccharin using 4.22 g (0.023 mol) of methyl6-chloroanthranilate in 22 ml of acetic acid and 40 ml of concentratedhydrochloric acid and 1.68 g (0.024 mol) of sodium nitrite in 7 ml ofwater to prepare the diazonium salt which was added to 1.93 g (0.011mol) of cupric chloride dehydrate and 6.5 g of sulfur dioxide in 30 mlof acetic acid and 5 ml of water. The resulting methyl2-chlorosulfonyl-6-chlorobenzoate was treated with 150 ml of ammoniumhydroxide as described above to afford 3.07 g (62%) of 4-chlorosaccharinas a pale yellow solid, mp 245°-246° C.

2-Hydroxymethyl-4-chlorosaccharin was prepared by heating a solution of1.00 g (0.0046 mol) of 4-chlorosaccharin and 3.22 ml of aqueous 37%formalin in ethanol. All attempts to crystallize the viscous oilyproduct resulted in decomposition to the starting material, and theproduct was thus used in the next step without characterization.

The crude 2-hydroxymethyl-4-chlorosaccharin so prepared (609 mg, 0.0025mol) was admixed with 5 ml of diethylether, and 3 ml of thionyl chloridewas added. The resulting mixture was heated to effect complete solution,stirred at room temperature overnight, diluted with 20 ml of ether andfiltered through a pad of celite topped with sand and eluted with ether.Removal of the solvent afforded 430 mg of crude chloromethyl derivative.A portion (225 mg) was removed for further reactions. The remainder (205mg) was flash chromatographed on silica gel and eluted with 40%ether/pentane to provide 137 mg of 2-chloromethyl-4-chlorosaccharin, mp135°-1360° C.

Preparation 3A

To a suspension of 6.0 g (0.03 mol) of cuprous iodide in 100 ml of THFwas added 25 ml of dimethyl sulfide, and the resulting yellow solutionwas cooled to -78° C. and treated dropwise with a solution of 23 ml(0.06 mol) of a 3.0M solution of phenyl magnesium bromide in diethylether. The resulting pale yellow-orange solution was stirred at -780° C.under nitrogen for one hour and then treated with 3.02 g (0.03 mol) of2-cyclohexenone in 10 ml of THF. The resulting mixture was allowed towarm to 0° C. over a two hour period, recooled to -780° C., treated with15 ml of hexamethylphosphoramide, stirred for thirty minutes, treatedwith 8.0 g (0.09 mol) of methyl cyanoformate and allowed to warm toambient temperature overnight. The reaction mixture was poured into 100ml of 2N hydrochloric acid, and the organic phase was separated and theaqueous phase backextracted with MDC. The combined organic extracts weretaken to dryness in vacuo and the residue triturated with saturatedammonium chloride, then with water, then with brine and taken to drynessonce again to give 3.2 g of methyl 2-phenylcyclohexan-6-one carboxylateas an oil.

The latter (3.0 g, 0.013 mol), 4.8 g (0.039 mol) of benzyl mercaptan and1.0 g of Amberlyst®15 resin (Rohm and Haas) in chloroform was heatedunder reflux for twenty hours, the mixture treated with an additional1.5 g of the resin and heated for an additional four hours. The mixturewas then cooled to ambient temperature, filtered, the filtrate taken todryness in vacuo, the residue triturated with hexane and the solidcollected by filtration to give 0.85 g (19%) of a mixture of methyl2-benzylthio-6-phenylcyclohex-2-ene carboxylate and methyl2-benzylthio-6-phenylcyclohex-1-ene carboxylate, 0.6 g (0.0018 mol) ofwhich was heated with 2.0 g of 2,3-dichloro-5,6-dicyanobenzoquinone in25 ml of toluene with stirring under nitrogen for twenty-four hours. Themixture was filtered through a pad of silica gel, eluting with 2:1MDC:hexane, and the eluate was taken to dryness to give 0.3 g (67%) ofmethyl 2-benzylthio-6-phenylbenzoate.

The latter (0.52 g, 0.0016 mol) dissolved in 10 ml of MDC was dilutedwith 20 ml of acetic acid and 5 ml of water, the mixture cooled to -100°C., and chlorine gas was bubbled through the mixture until theexothermic reaction subsided. The mixture was then stirred for tenminutes and taken to dryness in vacuo to give 0.41 g (85%) of methyl2-chlorosulfonyl-6-phenylbenzoate which was dissolved in 10 ml of THFand added to 25 ml of a solution of concentrated ammonium hydroxidewhile cooling in an ice/acetone bath. The reaction mixture was extractedwith MDC, the organic phase discarded, and the aqueous layer acidifiedto pH 1 with concentrated hydrochloric acid and extracted with MDC. Theorganic extracts, on washing with brine, drying and evaporation todryness, afforded 0.33 g (97%) of 4-phenylsaccharin.

Following a procedure similar to that described in Preparation 1, thelatter (0.33 g, 0.0012 mol) was reacted with 0.3 g (0.0019 mol) ofchloromethyl phenyl sulfide in 15 ml of toluene in the presence of 0.08g (0.0025 mol) of TBAB and the product,2-phenylthiomethyl-4-phenylsaccharin (0.48 g, 100%), treated withsulfuryl chloride in MDC to give 0.36 g (95%) of2-chloromethyl-4-phenylsaccharin.

Preparation 3B

To a suspension of anhydrous CuCN (2.16 g, 0.025 mol) in anhydrous ether(100 mi) at -780° C. was added tert butyllithium (29.0 mL of 1.7Msolution in pentane, 0.05 mol). After being stirred at -780° C. for 1 hrand at -450° C. for 30 minutes, the reaction mixture was recooled to-78° C. A solution of cyclohexenone (2.4 g,0.025 mol) in ether (25 mL)was added and stirring continued for 15 minutes at -78° C. and at -45°C. for 30 minutes. The resulting mixture was recooled to -78° C., andHMPA (10 mi) in ether (25 mL) was added. After 5 min, methylcyanoformate (2.55 g, 0.03 mol) in ether (25 mL) was added and thereaction warmed to 0° C. over a 2 hr period. The resulting mixture wasquenched with 2N HCl (100 mL), the layers were separated, and theorganic phase was washed with saturated NH₄ Cl solution (3×50 mi), water(2×50 mi), brine (1×50 mi) and dried (Na₂ SO₄). Removal of the solventin vacuo and purification by Kugelrohr distillation (bath temperature100°-1150° C. at 0.6 mm) afforded 4.7 g (88%) of methyl2-(1,1-dimethylethyl)cyclohexan-6-one-carboxylate.

The cyclohexanone (4.6 g, 0.022 mol) was mixed with benzylmercaptan(2.95 g, 0.024 mol) and the acidic clay montmorillonite, KSF (7.5 g) inanhydrous toluene (7.5 mL). The mixture was refluxed under nitrogen withazeotropic removal of water for 6 hr, cooled to room temperature and letstand overnight. The solids were filtered off and washed with ether. Thecombined filtrate was washed with 10% Na₂ CO₃, water, brine and dried.Removal of the solvent in vacuo and purification of the residue by flashchromatography on silica gel (10% ether in hexanes) gave 4.4 (66% of amixture of methyl 2-benzylthio-6-(1,1-dimethylethyl)cyclohex-2-enecarboxylate and 2-benzylthio-6-(1,1-dimethylethy l)cyclohex-1-enecarboxylate, which was stirred with DDQ (17.5 g, 0.077 mol) in toluene(50 mL) for 16 hr. The red reaction mixture was filtered through a 15 cmpad of silica gel, eluting with 6:3:1 hexanes:MDC:ether (1000 mL). Theeluents were washed with 10% NaOH solution, water, brine and dried.Removal of the solvent in vacuo and purification by chromatography onsilica gel (5% ether in hexanes) gave 1.6 g (40%) of methyl2-benzylthio-6-(1,1-dimethyl)benzoate.

The benzylthiobenzoate (1.3g, 0.004 mol) dissolved in MDC (5 mL) wasdiluted with acetic acid (25 mL) and water (2 mL), the mixture cooled to-10° C., and chlorine gas was bubbled until the exothermic reactionsubsided. the mixture was then stirred for 10 minutes and taken todryness in vacuo. Purification of the residue by flash chromatography onsilica gel (1:1 hexanes:MDC) gave 0.8 g (67%) of2-chlorosufonyl-6(1,1-dimethylethyl)benzoate, which was dissolved in THF(5 mL) and added to a solution of concentrated ammonium hydroxide (25mL) while cooling in an ice/acetone bath. After stirring at roomtemperature for 16 hr, the reaction mixture was concentrated in vacuoand acidified to pH 1 with 2N HCl. The separated solids were collectedby filtration and cystallized from ether to give 0.64 g (95%) of4-(1,1-dimethylethyl)saccharin, mp 185°-187° C.

The 4-(1,1-dimethylethyl)saccharin (0.025 g 1.0 mmol) was mixed withchloromethyl phenyl sulfide (0.25 g, 1.5 mmol) and tetrabutyl ammoniumbromide (0.2 g, 0.6 mmol) in toluene (25 mL) and refluxed under nitrogenfor 16 hr. The resulting mixture was cooled to room temperature,evaporated to dryness and purified by chromatography on silica gel (80%)MDC in hexanes) to give 0.35 g (98%) of2-phenylthiomethyl-4-(1,1-dimethylethyl)saccharin, which was treatedwith sulfuryl chloride (0.25 g, 1.8 mmol) in MDC to give 0.21 g (75%) of2-chloromethyl-4-(1,1-dimethylethyl)saccharin.

Preparation 4

A mixture of 3.22 g (0.012 mol) of 4-bromosaccharin (Japanese Pat.Publcn. 58/79,034, published May 12, 1983; C.A. 100, 7773w (1984)), 1.63g (0.015 mol) of potassium t-butoxide, 0.39 g (0.0012 mol) of TBAB and3.0 ml (0.022 mol) of chloromethyl phenyl sulfide in 100 ml of toluenewas heated under reflux under a nitrogen atmosphere for eight hours andthen stirred at ambient temperature for about sixteen hours. Thereaction mixture was then diluted with ethyl acetate, and the organiclayer was washed with dilute potassium carbonate, water and brine, driedover magnesium sulfate and taken to dryness in vacuo. The residual solidwas recrystallized from toluene-hexane to give 3.86 g (84%) of4-bromo-2-phenyl-thiomethylsaccharin, mp 174.5°-178° C.

To a solution of the latter (3.27 g, 0.0085 mol) in 85 ml of MDC wasadded, dropwise with stirring, 1.02 ml (0.0127 mol) of sulfurylchloride. The mixture was stirred at ambient temperature for an hour anda half, concentrated in vacuo and the residue triturated with hexane andfiltered to give 2.61 g of crude product which was recrystallized fromtoluene-hexane to give 2.24 g (85%) 2-chloromethyl-4-bromosaccharin,157°-159° C.

Preparation 5

To a solution of 8.0 ml (0.053 mol) of tetramethylethylenediamine(TMEDA) in 350 ml of THF at -70° C. was added 42 mi (0.055 mol) of a1.3M solution of s-butyl lithium in cyclohexane and the mixture wasstirred for fifteen minutes. To the solution was added dropwise withstirring a solution of 10.36 g (0.050 mol) of2-methoxy-N,N-diethylbenzamide in 150 ml of THF while maintaining thetemperature at -60° C. or below. After stirring for 20 minutes sulfurdioxide was bubbled into the reaction mixture, keeping the reactiontemperature below -50° C., until the reaction mixture was acid to wetlitmus paper. The mixture was stirred at ambient temperature for twohours, diluted with 450 ml of hexane, and the solid material which hadseparated was collected, dissolved in 200 ml of water and the mixturetreated with 65 g of sodium acetate and 21.5 g (0.19 mol) ofhydroxylamine-O-sulfonic acid in portions with stirring. The white solidwhich separated was collected and dried to give 7.04 g (49%) of2-aminosulfonyl-6-methoxy-N-,N-diethylbenzamide, mp 190°-194.5° C.

A mixture of the product (4.3 g, 0.015 mol) in 75 ml of dioxane and 25ml of concentrated hydrochloric acid was heated on a steam bath for 70hours, then cooled, concentrated in vacuo, diluted with water and iceand rendered strongly basic with concentrated sodium hydroxide. Themixture was washed with MDC, and the aqueous layer was acidified withdilute hydrochloric acid and extracted with MDC. The extracts were driedover magnesium sulfate and taken to dryness to give 1.29 g (40%) of4-methoxysaccharin. In an alternative, and preferred, procedure,cyclization of 2-aminosulfonyl-6-methoxy-N,N-diethylbenzamide to4-methoxysaccharin in 65% yield was carried out in refluxing glacialacetic acid for six and a half hours.

Following a procedure similar to that described in Preparation 4 above,1.14 g (0.0053 mol) of the latter was reacted with 1.31 ml (0.0097 mol)of chloromethyl phenylsulfide in toluene in the presence of 0.72 g(0.0064 mol) of potassium t-butoxide and 174 mg (0.00054 mol) oftetrabutylammonium bromide to give 1.23 g (69%) of4-5methoxy-2-phenylthiomethylsaccharin, mp 152.5°-154.50° C. (from ethylacetate-hexane), 1.02 g (0.003 mol) of which was treated with 0.36 ml(0.0045 mol) of sulfuryl chloride in MDC to give 282 mg (36%)of2-chloromethyl-4-methoxy-saccharin, mp 169°-1740° C.

Preparation 6A

To a solution of 4.74 ml (0.031 mol) of tetramethylethylenediamine in300 ml of THF (passed through alumina prior to use) was added 5.8 g(0.03 mol) of 2-ethyl-N,N-diethyl-benzamide. The solution was cooled to-78° C. and treated with 34.9 ml (0.031 mol) of a 0.9 M solution ofs-butyl lithium in cyclohexane. When addition was complete, the mixturewas stirred for twenty minutes and then treated with a solution of 3.2ml (0.04 mol) of ethyl iodide while maintaining the temperature at -78°C. The temperature was then allowed to rise to ambient temperature andthe mixture stirred for about sixteen hours and then poured into water.The resulting oil was separated and chromatographed on silica gel,eluting with 10% ethyl acetate/hexane to give 2.86 g (43%) of2-sec.-butyl-N,N-diethylbenzamide as a yellow oil.

Following a procedure similar to that described in Preparation 5 above,the latter (10.45 g, 0.045 mol), dissolved in 70 ml of THF, was added toa solution of 39.2 ml (0.047 mol) of a 1.2 M solution of s-butyl lithiumin cyclohexane and 7.1 ml (0.047 mol) of tetramethylethylenediamine in250 ml of THF while maintaining the temperature at -78° C. When additionwas complete the mixture was stirred for an additional one half hour at-78° C. and then treated with sulfur dioxide at -70° C. and then allowedto warm to room temperature. The mixture was taken to dryness in vacuo,and the residue was dissolved in water and added with stirring to a coldsolution of 15.2 g (0,134 mol) of hydroxylamine-O-sulfonic acid and 15.4ml (0.134 mol) of 35% sodium hydroxide to give 10.1 g (72%) of2-aminosulfonyl-6-sec.-butyl-N,N-diethylbenzamide.

The latter (6.83 g, 0.22 mol) was dissolved in 100 ml of glacial aceticacid and the solution heated under reflux for thirteen hours and thentaken to dryness. The residue was triturated with diethyl ether andcollected by filtration to give 5.7 q (83%) of the diethylammonium saltof 4-sec.-butylsaccharin.

The latter (3.0 g, 0.0096 mol), on reaction with 1.13 ml (0.012 mol) ofchloromethyl phenyl sulfide in toluene, afforded 3.47 g (100%) of2-phenylthiomethyl-4-sec.-butylsaccharin.

Reaction of the latter (3.2 g, 0.0097 mol) with 2.3 ml (0.029 mol) ofsulfuryl chloride in 20 ml of MDC afforded 2.4 g (87%) of2-chloromethyl-4-sec.-butylgarcharin.

Preparation 6B

By a procedure analogous to that described for Preparation 6A, 9.2 g(32.9 mmol) of 3,4,dimethoxy-2-propyl-N,N-diethylbenzamide was reactedwith sulfur dioxide and 5.6 g (49.4 mmol) of hydroxylamine-O-sulfonicacid to provide 7.4 q (63%) of2-aminosulfonyl-4,5-dimethoxy-6-propyl-N,N-dimethylbenzamide which wascyclized in quantitative yield in acetic acid and phenylthiomethylatedwith 1.42 mL (15 mmol) of chloromethyl phenyl sulfide to provide 4.07 gof 5,6-dimethoxy-2-phenylthiomethyl-4-propylsaccharin. Reaction of 3.59g (8.8 mmol) of the phenylthioether with 2.12 mL (26.4 mmol) sulfurylchloride provided 2.84 g (97%) of2-chloromethyl-5,6-dimethoxy-4-propylsaccharin.

The 3,4-dimethoxy-2-propyl-N,N-diethylbenzamide was obtained by thefollowing procedure:

To a solution of .216 moles of n-butyllithium in 250 mL of ether atambient temperature was added dropwise 138.2 g (0.216 mol) of veratrolin 100 mL of ether and 32.6 mL (0.216 mol) of TMEDA. The reaction wasstirred at 5ambient temperature 14 hours and 21.9 mL (0.225 mol) ofn-propyl iodide was added with cooling. The reaction was stirred 1 hourat RT and worked up with aqueous 1N HCl to give 14 g (36%) of2.3-dimethoxybenzenepropane which was brominated with 14.52 g (81.6mmol) of N-bromosuccinimide on 36 g of Kieselgel in 400 mL of CCl₄according to the method of Hisatoshi et al. [Bull. Chem. Soc. Jap.32,591-593 (1989)] to give 19.6 g (98%) of6-bromo-2,3-dimethoxybenzenepropropane.

The bromobenzene (14.2g, 54.8 mmol) was dissolved in 200 mL ether,cooled to -78°, and 25.2 mL (63 mmol) of 2.5 N n-butyllithium in hexanewas added. The reaction was warmed to 0°, held for an hour, and cooledto -70°, and 9 mL (71.2 mmol) of diethyl carbamyl chloride was added.The reaction was allowed to come to RT and was quenched with saturatedammonium chloride. After extraction and drying, the product wascrystallized from hexane to provide 9.5 g (62%) of3,4-dimethoxy-2-propyl-N,N-diethylbenzamide, mp 65°-67°.

Preparation 6C

By a process analogous to that of preparation 6B, 10.75 g (30 mmol) of6-aminosulfonyl-3,4-dimethoxy-2-isopropyl-N,N-diethylbenzamide wascyclized to provide 6.43 g of 5,6-dimethoxy-4-isopropyl saccharin (mp186-188 from ether-hexane), 5 g (17.5 mmol) of which wasphenylthiomethylated with 2.48 mL (26.3 mmol) ofphenylthiomethylchloride according to the procedure of Preparation 5,and chlorinated with 3 equivalents of sulfuryl chloride to provide an85% yield of 2-chloromethyl-5,6-dimethoxy-4-isopropylsaccharin, mp117°-119° from ethyl acetate-hexane.

The requisite benzamide was obtained from2,3-dimethoxy-α-methylbenzeneethane by bromination followed bycarbamylation as in Preparation 6B, to provide the intermediate3,4-dimethoxy-2-isopropyl-N,N-diethylbenzamide. A solution of 66 mL of0.96M sec-butyllithium was added to 16.1 g (57.6 mmol) of the benzamidein 400 mL of THF at -78° under nitrogen. After stirring 2 hours theorange anion was cannulated into excess sulfur dioxide at -60°. Thereaction was allowed to come to room temperature and stirred for 18 hrsto remove SO₂. Ten milliliters of sulfuryl chloride was added at 0° andthe reaction was stripped. The sulfonyl chloride was extracted intoEtOAc-ether, washed with water, dried and stripped. The residue wasdissolved in 80 mL of THF and 17 mL of conc. NH₄ OH was added at 0°. Thereaction was stirred briefly at RT, stripped, and triturated in 2:1ether-hexane to provide 12.89 g (62%) of 6-aminosulfonyl-3,4-dimethoxy-2-isopropyl-N,N-diethylbenzamide, mp138°-140°.

Preparation 7

To a solution of 9.3 ml (0.058 mol) of tetramethylethylenediamine in 340ml of THF at -78° C. was added 52 ml of a 1.1 M solution (0.057 mol) ofs-butyl lithium in cyclohexane. The solution was then treated with asolution of 11.37 g (0.052 mol) of 2-propyl-N,N-diethylbenzamide in 75ml of THF at -78° C. and the solution stirred for fifteen minutes andthen treated with a solution of 8.3 ml (0.104 mol) of ethyl iodide inTHF. The solution was stirred for an hour and a half at -78° C. and thenquenched by the addition of saturated ammonium chloride added dropwiseat -78° C. The mixture was then allowed to warm to ambient temperature,diluted with diethyl ether, washed first with dilute hydrochloric acid,then with water, then with saturated sodium bicarbonate, then withbrine, dried and taken to dryness to give 12.91 g of crude product whichwas chromatographed on silica gel, eluting with 10% ethyl acetate/hexaneto give 3.23 g (25%) of 2-(3-pentyl)-N,N-diethylbenzamide as a yellowoil.

Following a procedure similar to that described in Preparation 5 above,the latter (3.05 g, 0.0115 mol) in THF was reacted with 10.5 ml (0.126mol) of a 1.2 M solution of s-butyl lithium in cyclohexane in thepresence of 2.1 ml (0.014 mol) of tetramethylethylenediamine. Theresulting lithium salt was then reacted first with sulfur dioxide andthen with sodium hydroxylamine-O-sulfonate to give 1.97 g (52%) of2-aminosulfonyl-6-(3-pentyl)-N,N-diethylbenzamide as pale yellowcrystals, mp 118°-120° C. (soft 102°), 1.84 g (0.0056 mol) of which wascyclized in 22 ml of refluxing glacial acetic acid to give 1.28 g (70%)of the diethylammonium salt of 4-(3-pentyl)saccharin, mp 107.5°-109.5°C.

The latter (0.0037 mol), on reaction with 0.74 ml (0,0055 mol) ofchloromethyl phenyl sulfide in the presence of 116 mg (0.0004 mol) ofTBAB in 45 ml of toluene, afforded 1.93 g of2-phenylthiomethyl-4-(3-pentyl)saccharin as a pale yellow oil, 1.93 g(0.0037 mol) of which, on reaction with 0.59 ml (0.0073 mol) of sulfurylchloride in 37 ml of MDC, afforded 1.2 g of2-chloromethyl-4-(3-pentyl)saccharin as a pale yellow oil.

Preparation 2

A solution of 50.0 g (0.27 mol) of 2,4-dimethoxybenzoic acid in 60 ml(98.0 g, 0.82 mol) of thionyl chloride was heated under reflux for threehours, then cooled, and the excess thionyl chloride distilled off. Theresulting 2,4-dimethoxybenzoyl chloride was dissolved in 150 ml of MDCand the solution treated with a solution of 68 ml (48 g, 0.66 mol) ofdiethylamine in 500 ml of MDC, cooled to 0° C. When addition wascomplete the mixture was stirred for fifteen hours at ambienttemperature, then washed with saturated sodium bicarbonate, water andbrine and taken to dryness and the residue distilled in vacuo to give44.78 g (69%) of 2,4-dimethoxy-N,N-diethylbenzamide, b.p. 155°-163°C./0. 4 mm.

Following a procedure similar to that described in Preparation 5 above,10.0 g (0.042 mol) of the product in 250 mi of THF was reacted with40.57 ml of a 1.1 M solution (0.044mol) of s-butyl lithium incyclohexane and 6.35 ml (0.042 mol) of tetramethylethylenediamine inTHF. The resulting lithium salt was then reacted first with about 40 mlof sulfur dioxide and then with an aqueous solution (0.13 mol) of sodiumhydroxylamine-O-sulfonate to give 8.26 g of2-aminosulfonyl-4,6-dimethoxy-N,N-diethylbenzamide, 7.0 g of which(0.022 mol) was cyclized in 80 ml of refluxing glacial acetic acid togive 6.6 g (94%) of the diethylammonium salt of 4.6-dimethoxy-saccharinwhich was used as such in the next step without further purification.

The latter (6.0 g, 0.019 mol), on reaction with 3.82 ml (0.028 mol) ofchloromethyl phenyl sulfide in the presence of 0.611 g (0.0019 mol) ofTBAB in 200 ml of toluene, afforded 6.2 g (89%) of2-phenylthiomethyl-4,6-dimethoxysaccharin, 5.82 g of which (0.016 mol),on reaction with 3.23 g (0.0019 mol) of sulfuryl chloride in 100 ml ofMDC, afforded 4.63 g (100%) of 2-chloromethyl-4,6-dimethoxysaccharin,m.p. 185°-187° C.

Preparation 9A-9G

Following a procedure similar to that described above in Preparation 5,substituting for the 2-methoxy-N,N-diethylbenzamide used therein anappropriate 2-R⁴ -R⁵ -substituted-N,N-diethylbenzamide, the following2-halomethyl-4-R⁴ -R⁵ -saccharins listed in TABLE A were prepared viathe corresponding 2-phenylthiomethylsaccharins. Wherever available, themelting point, recrystallization solvent and yield are given for each ofthe 2-unsubstituted saccharins, the 2-phenylthiomethylsaccharins and the2-chloromethylsaccharins in columns headed "mp/Solv." and "Yield". Inall instances, the intermediate 2-phenylthiomethylsaccharins were useddirectly in the subsequent step without further characterization orpurification.

                                      TABLE A                                     __________________________________________________________________________              Sacc      2-C.sub.6 H.sub.5 SCH.sub.2 -Sacc                                                      2-ClCH.sub.2 -Sacc                               Prep                                                                             R.sup.4 /R.sup.5                                                                     mp/Solv                                                                             Yield                                                                             mp/Solv                                                                            Yield                                                                             mp/Solv  Yield                                   __________________________________________________________________________    9A H      260-262                                                                             93  --   100 158.0-160.0                                                                            51                                         7-Cl                      i-PrOH                                           9B CH(CH.sub.3).sub.2                                                                   177.0-178.0                                                                         88  --   100 93.0-96.0                                                                              100                                        H      MeOH               i-PrOH-Cyc hex                                   9C CH.sub.3 O                                                                           (a)   64  --   100 190.0-192.0                                                                            76                                         5-CH.sub.3 O                                                               9D COOCH.sub.3                                                                          (b)   76  --   65  186.0-187.0                                         H      EtOAc-hex                                                           9E C.sub.2 H.sub.5 O                                                                    (a)   96  --   95  139.0-140.0                                                                            97                                         H                                                                          9F (CH.sub.3).sub.2 CHO                                                                       87  --   75  142.5-143.5                                                                            94                                         H                                                                          9G C.sub.2 H.sub.5                                                                      i-PrOH                                                                              67  --   52  --       99                                         5,7-(CH.sub.3 O).sub.2                                                     __________________________________________________________________________     (a) Isolated and used in the next step as the diethylammonium salt.           (b) The 2unsubstituted-saccharin was prepared by cyclization of dimethyl      3aminosulfonylphthalate in methanol in the presence of a molar equivalent     of sodium methoxide. The phthalate ester was prepared by diazotization of     dimethyl 3aminophthalate, decomposition of the diazonium salt with sulfur     dioxide in the presence of cupric chloride and reaction of the resulting      dimethyl 2chlorosulfonylphthalate with ammonia. (84% yield overall).     

Preparation 10

Following a procedure similar to that described in Preparation 2,reaction of 18.3 g (0.1 mol) of saccharin with 70 ml of 37% formalin inethanol afforded 3.58 g (70%) of 2-hydroxymethylsaccharin. The latter(25 g, 0.117 mol) was reacted with 63.3 g (0.234 mol) of phosphorustribromide in diethyl ether to give 29.8 g (92%) of2-bromomethylsaccharin, mp 155°-157° C.

Preparation 11

To a solution of 4 g (0.0175 mol) of 6-nitrosaccharin in 240 ml ofethanol was added 4.4 g (0.0175 mol) of thallium ethoxide, and themixture was allowed to stand at room temperature for one hour, cooledfor about 16 hours and the precipitated solid collected and dried togive 7.6 g (100%) of the thallium salt of 6-nitrosaccharin. The productwas suspended in 50 ml of DMF and the mixture treated with 3.07 g(0.0194 mol) of chloromethyl phenyl sulfide, the mixture warmed at about63°°C. for five hours, allowed to stand at ambient temperature for about16 hours, and then poured into ice water. The crude product, obtained byfiltration, was stirred in MDC and filtered to remove thallium salts,The filtrate was freed of solvent, and the resultant pale yellow solidwas sonicated with warm ethanol and once again collected and dried togive 4.6 g (75%) of 6-nitro-2-phenylthiomethylsaccharin, mp 161°-163° C.The latter, on reaction with sulfuryl chloride in MDC using theprocedure described above in Preparation 4, afforded 3.7 g of2-chloromethyl-6-nitrosaccharin.

Preparation 12

A solution of 49.8 g (0.199 mol) of2-hydroxy-5-(1,1,3,3-tetramethylbutyl)benzoic acid in 200 ml of methanolwas heated to 50° C. and then treated dropwise with about 80 g ofsulfuric acid at a rate to maintain the reaction under reflux. Thereaction mixture was heated under reflux for an additional 11 hours,then cooled and partitioned between water and ethyl acetate. The organiclayer was washed with saturated sodium bicarbonate, then with brine,dried over sodium sulfate and taken to dryness to give 48.6 g (92%) ofmethyl 2-hydroxy-5-(1,1,3,3-tetramethylbutyl)benzoate.

The latter dissolved in 250 ml of DMF was treated first with 40.4 g(0.36 mol) of 1,4-diazabicyclo[2.2.2]octane followed by 33.4 g (0.27mol) of N,N-dimethylchlorothiocarbamate and 100 ml of DMF. The reactionmixture was heated at 450C for about eight hours, cooled, poured intoice/water-and concentrated hydrochloric acid and then extracted withethyl acetate. The combined organic extracts were washed with dilutehydrochloric acid, then with sodium bicarbonate and then with brine,dried and taken to dryness to give 48.2 g (76%) of methyl2-(N,N-dimethylthiocarbamyloxy)-5-(1,1,3,3-tetramethylbutyl)benzoatewhich was heated at 220° C. for 15 hours, then cooled, dissolved intoluene and chromatographed on silica, eluting with 1:9 ethylacetate:toluene, to give 3.6 g (14%) of methyl2-(N,N-dimethylcarbamylthio)-5-(1,1,3,3-tetramethyl)benzoate.

A solution of the latter (0.025 mol) in 40 ml of MDC was treated, withstirring, with 80 ml of glacial acetic acid, followed by 16 ml of water.The reaction mixture was cooled to 0° C., and chlorine was bubbledthrough the reaction mixture for about five minutes while maintainingthe temperature between 5° and 24° C. The reaction was stirred for anadditional 30 minutes, concentrated in vacuo, and the remaining solutionpoured into ice water. Extraction of the mixture with ethyl acetate andisolation of the product from the combined organic extracts afforded 6.8g (78%) of methyl 2-chlorosulfonyl-5-(1,1,3,3-tetramethylbutyl)benzoate.

The product (9.0 g, 0.026 mol) was dissolved in THF and added to 100 mlof concentrated ammonium hydroxide with cooling in an ice bath. Theresulting solution was stirred for about 16 hours, then concentrated invacuo and the concentrated solution acidified to pH 3 with concentratedhydrochloric acid. The mixture was stirred for several hours, and theseparated solid collected, washed with water and dried to give 9.0 g of5-(1,1,3,3-tetramethylbiatyl)saccharin, mp 213°-215° C.

Following a procedure similar to that described in Preparation 11, 9.0 g(0.30 mol) of the product was reacted with thallium ethoxide in ethanoland the resulting thallium salt reacted with 3.33 g (0.021 mol) ofchloromethyl phenylsulfide in DMF to give 5.76 g (66%) of2-phenylthiomethyl-5 (1,1,3,3-tetramethylbutyl)saccharin, 3.3 g (0.007mol) of which was treated with 0.944 g of sulfuryl chloride in MDC togive 1 g (41%) of 2-chloromethyl-5-(1,1,3,3-tetramethyl-butyl)-saccharin.

Preparation 13

Following a procedure similar to that described in Preparation 12 above,15.5 g (0.086 mol) of ethyl 2-hydroxy-6-methylbenzoate was reacted with15.9 g (0.129 mol) of N,N-dimethylchlorothiocarbamate in the presence of19.3 g (0.172 mol) of 1,4-diazabicyclo(2.2.2)octane in DMF to give 22.1g (96%) of ethyl 2-(N,N-dimethylthiocarbamyloxy)-6-methylbenzoate whichwas heated at 220° C. for about 10 hours. The product was purified bychromatography on silica gel in MDC to give ethyl2-(N,N-dimethylcarbamylthio)-6-methylbenzoate as a red-brown oil.

A solution of the latter (22.6 g, 0.0844 mol) in 170 ml of MDC wastreated with 340 ml of glacial acetic acid and 68 ml of water whilecooling in an ice/acetone bath, and chlorine was bubbled through thereaction mixture for 10-15 minutes. The reaction vessel was evacuated toremove excess chlorine and MDC and the mixture poured into water andpartitioned between MDC and water. The organic layer, on drying andevaporation to dryness, afforded 19 g of ethyl2-chlorosulfonyl-6-methylbenzoate, 5 g (0.019 mol) of which was reactedwith concentrated ammonium hydroxide in THF to give 6.1 g (67%) of4-methylsaccharin.

Following a procedure similar to that described in Preparation 11 above,the product (10.1 g, 0.0512 mol) was converted to the thallium salt byreaction with 12.8 g (0,0512 mol) of thallium ethoxide in ethanol andthe thallium salt reacted with 6.7 g (0.0427 mol) of chloromethyl phenylsulfide in DMF to give 6.85 g (50%) of2-phenylthiomethyl-4-methylsaccharin.

Reaction of the latter (6.7 g, 0.021 mol) with sulfuryl chloride in MDCafforded 4.9 g (95%) of 2-chloromethyl-4-methylsaccharin.

Preparation 14A

A mixture of 75 g (0.36 mol) of 3,3-dithiobispropionic acid, 102 ml ofthionyl chloride and a catalytic amount of pyridine was stirred forabout 24 hours and then evaporated to dryness in vacuo, The residue wastreated with MDC and evaporated to dryness again to remove residualthionyl chloride and pyridine to give 87 g (98%) of the correspondingbis acid chloride, 44.8 g (0.18 mol) of which was dissolved in THF andadded dropwise to a solution of 77.16 g (0.72 mol) of benzylamine inTHF. The mixture was stirred for two hours at 40°-45° C., cooled and theprecipitated solid collected, washed with water and dried to give 59 g(84%) of 3.3-dithiobis-propionic acid N,N'-dibenzylcarboxamide, mp162°-165° C.

Reaction of 7.0 q (0.018 mol) of the latter with 10.25 g (0.076 mol) ofsulfuryl chloride in MDC gave a mixture of 2-benzyl-2H-isothiazol-3-oneand 5-chloro-2-benzyl-2H-isothiazol-3-one which were largely separatedfrom one another by sonication in MDC (which solubilized most of theformer). The insoluble material was collected by filtration andchromatographed on silica gel with MDC. There was thus obtained5-chloro-2-benzyl-2H-isothiazol-3-one, mp 58°-680° C.

A solution of 10 g (0.044 mol) of the latter in MDC was cooled to 0° C.and the solution treated with 7.6 g (0.044 mol) of 3-chloroperbenzoicacid, the mixture stirred for 10 minutes and then treated with a second7.6 g portion of the perbenzoic acid. The reaction mixture was filtered,the filter washed with MDC and the filtrate washed with saturated sodiumbicarbonate, then with brine, dried over sodium sulfate and taken todryness and the residue chromatographed in MDC on silica gel, theproduct being eluted with 50:50 hexane:MDC, to give 7.15 g (46%) of5-chloro-2-benzyl-2-H-isothiazol-3-one-1-oxide.

A solution of 1.1 g (0.0045 mol) of the latter in 8 ml of benzene wastreated with 0.55 g (0.0051 mol) of 2methoxyfuran and the solutionheated in a pressure bottle at 70° C. for 1.5 hours and then cooled andthe solid collected, washed with benzene and dried to give2-benzyl-7-hydroxy-4-methoxybenzisothiazol-3-one-1-oxide, mp 235°-237°C.

A mixture of the product (1.85 g, 0.006 mol), 2,48 g (0.018 mol) ofpotassium carbonate and 1.70 g (0.012 mol) of methyl iodide in acetonewas heated under reflux for 1.5 hours and then cooled and poured intowater. The solid which separated was collected by filtration, washedwith water and dried to give 1.70 g (89%) of2-benzyl-4,7-dimethoxybenzisothiazol-3-one-1-oxide, 1.13 g (0.0035 mol)of which was oxidized with 1.20 g (0.007 mol) of 3-chloroperbenzoic acidin MDC using the procedure described above to give 1.03 g (88%) of2-benzyl-4.7-dimethoxysaccharin.

A mixture of 2.07 g (0.0062 mol) of the product, 1.37 g (0.02 mol) ofammonium formate and 1.5 g of 10% palladium-on-charcoal catalyst in 80ml of methanol was heated under reflux for one hour, then cooled andfiltered, and the filtrate taken to dryness to give 0.92 g (57%) of theammonium salt of 4,7-dimethoxysaccharin.

A solution of 1.11 g (0.0042 mol) of the ammonium salt was dissolved inDMF, 0.67 g (0.0042 mol) of chloromethyl phenyl sulfide was added, andthe solution heated under reflux for eight hours and then cooled andpoured into ice water. The solid which separated was collected, washedwith water and dried to give 0.50 g (33%) of 2-]phenyl-4,7-dimethoxysaccharin,

Reaction of the latter (0.5 g, 0.0013 mol) with sulfuryl chloride in MDCusing the procedure described above in Preparation 4 afforded 0.22 g(58%) of 2-chloromethyl-4,7-dimethoxysaccharin.

Preparations 14B and 14C

Following a procedure similar to that described in Preparation 14A,other 2-chloromethylsaccharin derivatives were prepared as follows:

Preparation 14B

Reaction of 5.8 g (0.024 mol) of5-chloro-2-benzyl-2H-isothiazol-3-one-1-oxide with 3.76 g (0.0335 mol)of 2-ethoxyfuran afforded 3.05 g (40%) of2-benzyl-4-ethoxy-7-hydroxybenzisothiazol-3-one-1-oxide, 5.7 g of whichwas reacted with 3.6 g 10.0197 mol) of 2-[2-methoxyethoxy]ethyl bromidein the presence of 4.95 g (0.0358 mol) of potassium carbonate in 125 mlof methyl ethyl ketone and 25 ml of DMF to give 7.0 g (93%) of2-benzyl-A-ethoxy-7-[2-(2-methoxyethoxy]benzisothiazol-3-one-1-oxide,which was oxidized as before with 3-chloroperbenzoic acid in MDC to give2-benzyl -f2-(2-methoxyethoxy)ethoxylsaccharin. Debenzylation of 6.6 g(0.015 mol) of the latter with 3.34 g (0.053 mol) of ammonium formate inthe presence of 6.4 g of 10% palladium-on-charcoal catalyst in methanolafforded the ammonium salt of4-ethoxy-7-r2-(2-methoxyethoxy)ethoxy]saccharin, which was reacted with2.38 g (0.015 mol) of chloromethyl phenyl sulfide in 100 mL of DMF togive 1.46 g (21%) of2-phenylthiomethyl-4-ethoxy-7-[2-(2-methoxyethoxy)-ethoxy]saccharin, mp73°-75° C. (from isopropanol). Treatment of 1.4 g (0.0029 mol) of theproduct with 0.4 g (0.0029 mol) of sulfuryl chloride in MDC afforded1.16 g (100%)2-chloromethyl-4-ethoxy-7-[2-(2-methoxyethoxy)ethoxy]-saccharin.

Preparation 14C

Reaction of 3.03 g (0.01 mol) of2-benzyl-7-hydroxy-4-methoxybenzisothiazol-3-one-l-oxide (Preparation14A) with 2.01 g (0.011 mol) of 2-(2-methoxyethoxy)ethyl bromide inmethyl ethyl ketone in the presence of 2 g (0.015 mol) of potassiumcarbonate afforded 2.58 g (64%) of2-benzyl-4-methoxy-7-[2-(2-methoxyethoxy)ethoxy]benzisothiazol-3-one-1-oxide,which, on oxidation with 1.1 g (0.0063 mol) of 3-chloroperbenzoic acidin MDC, gave 2-benzyl-4-methoxy-7-[2-(2-methoxyethoxy)ethoxy]saccharin.Debenzylation of 0.25 g (0.0006 mol) of the product with 0.13 g (0.0021mol) of ammonium formate in methanol in the presence of 0.25 g of 10%palladium-on-charcoal gave 0.21 g (100%) of the ammonium salt of4-methoxy-7-[2-(2-methoxyethoxy)ethoxy]saccharin. Reaction of 1.4 g(0.004 mol) of the ammonium salt with 0.63 g (0.004 mol) of chloromethylphenyl sulfide in DMF afforded2-phenylthiomethyl-4-methoxy-4-[2-(2-methoxyethoxy)ethoxy]saccharin,which, on reaction with sulfuryl chloride in MDC, afforded 0.53 g (35%)of 2-chloromethyl-4-methoxy-7-[2-(2-methoxyethoxy) ethoxylsaccharin.

Preparation 15

A solution of 1.89 g (0.011 mol) of diethylamino sulfur trifluoride(DAST) in 20 ml of MDC was added to a suspension of 2.13 g (0.01 mol) of2-hydroxymethylsaccharin in 25 ml of MDC while maintaining the reactionmixture at -78° C.

The reaction mixture was stirred at -78° C. for one hour, thetemperature allowed to slowly rise to ambient temperature, the mixturestirred for 16 hours and then poured into ice-water. The organic layerwas separated and washed with water, dried over magnesium sulfate andtaken to dryness to give 2.2 g of product which was recrystallized fromethyl acetate to give 1.6 g (74%) of 2-fluoromethylsaccharin, mp 96°-98°C.

Preparation 16A

To a solution of 0.5 g (0.0025 mol) of 4-methylsaccharin in THF cooledto -78° C. by a dry ice/acetone bath was added, dropwise with stirring,a solution of 5.2 ml of 10 a 1.3 M solution of s-butyl lithium incyclohexane. The mixture was stirred an additional hour at -78° C. andthen treated with 0.16 ml (0.025 mol) of methyl iodide over a 11/2 hourperiod. The mixture was stirred for an hour and 45 minutes, quenched in25 ml of 1N hydrochloric acid, the reaction mixture rendered basic, theaqueous mixture extracted with chloroform and then acidified andextracted with ethyl acetate. The combined organic extracts were washedwith 10% sodium thiosulfate, then with brine, dried over sodium sulfateand taken to dryness to give a product, whose PMR spectrum indicated amixture consisting of 74% of 4-ethylsaccharin and 21% of4,7-dimethylsaccharin.

Following a procedure similar to that described in Preparation 4 above,the crude material (0.47 g, 0.0022 mol) was reacted with 0.24 ml (0.0028mol) of chloromethyl phenylsulfide in toluene in the presence oftetrabutylammonium bromide, and the product chromatographed on silicagel, eluting with MDC, 5 ml fractions being collected. The first 420 mlof eluate were discarded. The next 20 fractions, on evaporation,afforded 0.07 g of material, predominantly2-phenylthiomethyl-4,7-dimethylsaccharin, which was set aside. The next25 fractions afforded 0.37 g of 2-Rhenyl 1-4-ethylsaccharin, which wasreacted with sulfuryl chloride in MDC to give 0.19 g (66%) of2-chloromethyl-4-ethylsaccharin,

Preparation 16B

Following a procedure similar to that described in Preparation 16A, 10 g(0.051 mol) of 4-methylsaccharin in THF was reacted with 86 ml (0.10mol) of a 1.18 M solution of s-butyl lithium in cyclohexane and theresulting solution treated with 4.5 ml (0.050 mol) of ethyl iodide togive 10.15 g (89%) of 4-prolpylsaccharin, which, on reaction with 5.32ml (0.056 mol) of chloromethyl phenyl sulfide in toluene in the presenceof tetrabutylammonium bromide, afforded a crude mixture from which wasisolated by flash chromatography on silica gel2-Rhenylthiomethyl-4-propylsaccharin as an oil, 1.8 g (0.0052 mol) ofwhich, on reaction with 1.25 ml (0.016 mol) of sulfuryl chloride in MDC,afforded 0.94 g (66%) of 2-chloromethyl-4-propylsaccharin.

Preparation 16C

A preferred alternative to preparation 16A is as follows:

To a solution of 5.13 g (25 mmol) of N,N,2-triethylbenzamide in THF (50mi) at -78° was added a solution of LDA (Aldrich 2.OM, 15.63 mL, 31.25mmol). The solution was warmed to -10° C. with ice water over 1 hr, thencooled to -78° C. with dry ice-acetone. TMSCl (6.34 mL, 50 mmol) wasadded neat at -78° C. and then reaction brought to room temperatureafter 1 hr. The reaction was quenched with saturated NH₄ Cl andextracted with ether (2×100 mL), dried over MgSO₄, stripped and theresidue distilled in a Kugelrohr (130°-140° C., 0.65 mm) to obtain 6.51g (94%) of N,N-diethyl-2-[1-(trimethylsilyl)ethyllbenzamide.

To a solution of sec-BuLi (0.97M, 5.10 mL, 4.96 mmol) and TMEDA (0.75mL, 4.96 mmol) in THF at -78° C. was added the amide (1.25 g, 4.50 mmol)in THF. Excess SO₂ in THF was added quickly at -78° C. then warmed toroom temperature. The THF was removed in vacuo and the residue treatedat 0° C. with two equivalents of a 1:1 solution of sodium hydroxide(0.36 g, 9.0 mmol) and hydroxylamine-O-sulfonic acid (1.0 g, 9.0 mmol)in H20, The reaction was stirred at room temperature for 4 hrs,extracted with EtOAc, dried over MgSO₄, concentrated and flashchromatographed on silica gel with 20% ethyl acetate/hexane to give 0.62g (41%) of2-aminosulfonyl-N-N-diethyl-6-[1-(trimethylsilyl)ethyl]benzamide. Thebenzamide (0.95 g, 2.66 mol) was refluxed in glacial acetic acid (20 mi)for 18 hr, stripped to dryness, triturated with hot cyclohexane (30 mi)and a trace of EtOAc (3 mi), cooled with scratching and filtered. Therewas obtained 0.81 g (85%) of 4-[1-(trimethylsilyl)ethyl]saccharin, mp123°-125° C.

To the trimethylsilylethylsaccharin (0.25 g, 0.70 mmol) in DMF (9 mi) atroom temperature was added H₂ O (1 mL) and cesium fluoride (0.75g 4.94mmol, 7 equivalents). After 7 hr the reaction was poured into 5% NAOHand extracted with EtOAc. The aqueous layer was acidified with 12N HCland extracted with Et₂ O-EtOAc (1:1), dried over Na₂ SO₄, filtered andstripped to give a colorless solid in quantitative yield. It wasrecrystallized from 5% Et₂ O-hexanes to give 0.091 q (64%) of4-ethylsaccharin, mp 183°-185° C.

Preparation 17

The 0.07 g sample of material obtained in the early fractions from thechromatographic separation described above in Preparation 16A consistingpredominantly of 2-phenylthiomethyl-4,7-dimethylsaccharin was reactedwith 0.05 ml of sulfuryl chloride in MDC and the product recrystallizedfrom cyclohexane-ethyl acetate to give 20 mg (51%) of2-chloromethyl-4,7-dimethylsaccharin, mp 107°-108° C.

Preparation 18A

To a solution of 40.0 g (0.174 mol) of 2-isopropyl-4-methoxybromobenzenein 600 ml of diethyl ether at 0° C. was added 103.68 ml (0.175 mol) of a1.69 M solution of butyl lithium in diethyl ether. When the addition wascomplete the solution was cooled to 0° C. for one hour and stirred foran additional five hours at ambient temperature, then recooled to -78°C. and treated with a solution of 23.68 g (0.175 mol) ofN,N-diethylcarbamyl chloride in 80 ml of diethyl ether. The resultingsolution was stirred for about 12 hours while the reaction temperaturewas allowed to rise and then quenched with saturated ammonium chloridesolution. The aqueous and organic layers were separated, the aqueouslayer back extracted with ethyl acetate and the combined organicextracts washed once with brine, then dried and the solution taken todryness to give a crude product which was flash chromatographed onsilica gel, eluting with 30% ethyl acetate/hexane to give 34.4 g (79%)of 2-isopropyl-4-methoxy-N,N-diethylbenzamide as an oil which was usedas such in the next step without further purification. The oil can bedistilled, if desired, and boils at 123-129/0.2-0.3 mm.

Following a procedure similar to that described in Preparation 5 above,the latter (15.0 g, 0.060 mol) in 100 ml of diethyl ether was reactedwith 77.8 ml (0.784 mol) of a 1.2M solution of s-butyl lithium incyclohexane in the presence of 6.98 g (0.06 mol) oftetramethylethylenediamine. The resulting lithium salt was then reactedfirst with 50 ml of sulfur dioxide and then with 0.181 mol of sodiumhydroxylamine-O-sulfonate to give 11.6 g (59%) of2-aminosulfonyl-6-isopropyl-4-methoxy-N,N-diethylbenzamide, m.p.103°-105° C. (from ethyl acetate/hexane). Eleven grams (0.034 mol) ofthe benzamide was cyclized in 200 ml of refluxing glacial acetic acid togive 10.3 g of the diethylammonium salt of4-isopropyl-6-methoxysaccharin, m.p. 132°-135° C.

The latter (0.030 mol), on reaction with 6.14 ml (7.25 g, 0.046 mol) ofchloromethyl phenyl sulfide in the presence of 0.98 g (0.003 mol) ofTBAB in 250 ml of toluene, afforded 10.1 g (88%) of2-phenylthiomethyl-4-isopropyl-6-methoxysaccharin as an oil, 9.7 g(0.026 mol) of which, on reaction with 3.1 ml (5.21 g, 0.039 mol) ofsulfuryl chloride in MDC, afforded 6.9 g (88% of2-chloromethyl-4-isopropyl-6-methoxysaccharin, mp 151°-152° C.

Preparation 18B

An alternative procedure was also followed:

To a solution of 300 mL of N,N,N',N'-tetramethylethylenediamine (TMEDA)(1.99 moles) in 4 L of anhydrous ether was added 1550 mL of sec-BuLi(1.3 M) and the system was cooled to -70° C. under a nitrogenatmosphere. 15 A solution of 454.2 g of 2-isopropyl-4-methoxyN,N-diethylbenzamide (1.82 moles) in 300 mL of anhydrous ether was addeddropwise over 30 minutes (the temperature was maintained at or below-60° C. during the addition). After the addition was complete, thereaction was stirred at -70° C. for one hour and allowed to warm to -50°C. After holding the temperature at -50° C. for 30 minutes, the mixturewas cooled back to -70° C. To this stirred solution was added viacannulating tube a solution of 200 g of SO₂ in 200 mL of dry etherprecooled to -40° C. under positive nitrogen pressure over a 20-minuteperiod. The temperature of the reaction mixture during the addition wasmaintained below -40° C. (A white powdery precipitate of aryllithiumsulphinate separated out almost immediately). After the addition, theicebath was removed and the reaction was allowed to stir at ambienttemperature for two hours. It was cooled to -50° C. and to this stirredsolution was added 190 mL of sulfuryl chloride (2,36 moles) dropwiseover a 15-minute period maintaining the temperature below 10° C. duringthe addition. After further stirring for 30 minutes at 0°-50° C., awhite insoluble precipitate was filtered off and washed with 2 L ofanhydrous ether. Removal of the solvent at atmospheric pressure affordedthe sulfonyl chloride as a crude dark oil. This crude sulfonyl chloridewas dissolved in 1.4 L of THF, cooled to -10° C., and 540 mL ofconcentrated NH₄ OH (28%) was added in portions over 15 minutes (thetemperature was kept at 15° C. or below throughout the addition) .Afterstirring for 15 minutes at ambient temperature, the THF and excessammonia were removed under vacuum to give a dark oil, which was dilutedwith 6.0 L of water and acidified with 3N HCl to pH 1. The light yellowsolid was collected by filtration and washed with 800 mL of water. Thesolid was dried at 60° C. under vacuum for 18 hours and recrystallizedfrom a mixture of 800 mL of ethyl acetate and 3 L of hexane to give 429q (72%) of 2-aminosulfonyl-6-isopropyl-4-methoxy-N,N-diethylbenzamide,mp 122°-125° C.

A solution of 429.6 g of the diethylbenzamide (1.31 mole) in 1.5 L ofacetic acid was refluxed for 20 hours. It was cooled to room temperatureand the solvent removed under vacuum. The oily residue was dissolved in6 L of water and adjusted to pH 1 with 6N HC1. The crude product wascollected by filtration and washed with 2 L of water. The solid wasdried at 60° C. under vacuum for 18 hours and recrystallized from ethylacetate/hexane to give 303 g (91%) 4-isopropyl-6-methoxysaccharin, mp188°.

To a suspension of 24 g of paraformaldehyde (0.8 mole) and 86.4 g ofchlorotrimethylsilane (1.6 moles) in 200 mL of 1,2-dichloroethane wasadded 0.8 ml anhydrous tin(IV) chloride and the resulting solutionstirred on a steam bath for one hour. At the end of this period, 51 g of4-isopropyl-6-methoxysaccharin (0.2 mole) was added to the clearsolution and the reaction mixture was further refluxed for 18 hours. Itwas cooled to room temperature, poured into water, the organic layerseparated and washed with 50 mL of 2N sodium hydroxide solution. Theorganic layer was dried over anhydrous magnesium sulfate andconcentrated under vacuum to give crude product. It was purified bycrystallization from ethyl acetate/hexane to give 57 g (87%) of2-chloromethyl-4-isopropyl-6-methoxysaccharin, mp 151.

Preparation 19

To a solution of 1.0 g (0.0039 mol) of 4-isopropyl-6-methoxysaccharin in15 ml of MDC was added at ambient temperature 1.28 g (5.12 ml) of a 1 Msolution of boron tribromide in MDC. When addition was complete thereaction mixture was heated under reflux for about five hours, cooled,taken to dryness in and the residue treated with ice and saturatedsodium bicarbonate. The aqueous solution was extracted once with ethylacetate and then acidified to pH 1 with concentrated hydrochloric acid.Extraction of the mixture with ethyl acetate/.diethyl ether (8:2),drying the organic extracts and removal of the solvent in vacuo afforded0.9 g (96%) of 6-hydroxy-4-isopropylsaccharin as a white crystallinesolid which was used as such in the next step.

An alternative procedure was also used. To a stirred suspension of 62.74g (0.47 mol) of AlCl₁₃ in 500 mL of chloroform at 0° was added 43.9 g(0.7 mol) of ethanethiol. Within minutes a clear solution formed. Tothis a solution of 20.0 g (0.078 mol) of 4-isopropyl-6-methoxysaccharinin 550 mL of chloroform was added over a 30-min period. This solutionwas allowed to warm to RT and stirred for 3-4 hr at 60°. After cooling,the mixture was poured into ice-water and acidified with dilute HCl. Thesolid which separated was collected by filtration, washed with water anddried to give 18.4 g (97%) of 6-hydroxy-4-isopropylsarcharin.

Following a procedure similar to that described in Preparation 4 above,the latter (0.004 mol) was reacted with 0.61 ml (0.0046 mol) ofchloromethyl phenyl sulfide in toluene in the presence of 0.133 g (0.004mol) of TBAB to give 0.32 q (21%) of4-isopropyl-6-hydroxy-2-phenylthiomethylsaccharin, m.p. 127°-129.5, 1.78g of which was treated with 0.43 ml (0.73 g) of sulfuryl chloride in MDCto give 1.2 g (84%) of 2-chloromethyl-4-isopropyl-6-hydroxysaccharin,m.p. 149°-150° C.

Preparation 22

Five grams (0.0207 mol) of 6-hydroxy-4-isopropylsaccharin was dissolvedin 150 mi of methanol and 3.4 g (0.0104 mol) of Cs₂ CO₃ was added. Themixture was stirred for 3-4 hr at RT. The excess methanol was removedunder reduced pressure and the residue was dried for 2 hr under highvacuum. The residue was then dissolved in 110 mL of DMF and 0.32 g(0.0209 mol) of chloromethyl phenyl sulfide was added. The stirredmixture was heated at 70°-750° for 12 hr, cooled, treated with ice waterand extracted with 600 mL of 4:1 ethyl acetate:ether. The organic layerwas washed with water and saturated NaCl and dried. The solvent wasremoved under reduced pressure. The residue was purified by flashchromatography with 20% ether in MDC. There was obtained 4.5 g (60%) of4-isopropyl-6-hydroxy-2-phenylthiomethylsaccharin, mp 150°-151.5° C.which, on reaction with sulfuryl chloride as described in Preparation19, yielded 2-chloromethyl-4-isopropyl-6-hydroxysaccharin as before.

Preparation 23

To a solution of 5-chloro-2-benzyl-4-isothiazolin-3-one (J. Het. Chem.8, 571, 1971) (9.4 g, 0.04 mol) in MDC (100 mL) was added in one portion80-85% 3-chloroperoxybenzoic acid (10.8 g, 0.06 mol) and the resultingmixture stirred at room temperature overnight under nitrogen. Theprecipitated solids were filtered off and washed with MDC (50 mi). Thecombined filtrate was evaporated to near dryness and the residuepartitioned between ethyl acetate (300 mi) and saturated NaHCO₃ (100mL). The layers were separated and the organic phase washed withsaturated NaHCO₃ (2×100 mL), brine (1×100 mL) and dried. Removal of thesolvent in vacuo afforded 10.0 g (99%) of5-chloro-2-benzyl4-isothiazolin-3(2H)-one 1-oxide as a pale yellow oil.

The 1-oxide (10.0 g, 0.04 mol) in glacial acetic acid (200 mi) wastreated with 30% H₂ O₂ (100 mL, 0.88 mol) and heated on a steam bath for2 hr during which time an additional 30 mL (0.26 mol) of 30% H₂ O₂ wasadded. After heating on a steam bath for an additional hour, thereaction mixture was cooled to room temperature and poured into ice coldwater (1L) and stirred. The precipitated solids were collected byfiltration, washed with water (2×100 mL), hexanes and air dried to give4.8 q (45%) of 5-chloro-2-benzyl-4-isothiazolin-3(2H)-one 1,1-dioxide asa colorless solid.

The dioxide (1.2 g 4.7 mmol) was mixed with 2,02 (11 mmol) of2-trimethylsiloxy-5-methyl-hexa-1,3-diene (prepared from5-methyl-hex-3-ene according to the method of E. J. Corey et al., Tet.Lett. 495, 1984) in toluene (50 mL) and refluxed for a period of 20 hrunder nitrogen. The 15 resulting mixture was cooled to room temperatureand concentrated in vacuo. The residue was dissolved in THF (25 mi) andtreated with 2N HCl (10 mi). After stirring under nitrogen at roomtemperature for 10 min, ether (100 mi) was added and the layersseparated. The organic phase was washed with water, brine, dried andevaporated to dryness to give a pale yellow foam. The foam was dissolvedin toluene (30 mi), DBN (1.5 mi) was added and stirred at roomtemperature for 2 hr. MDC (100 mi) and 2N HCl (50 mL) were added andstirring continued for 5 min. The layers were separated and the organicphase washed with water, brine and dried. Removal of the solvent invacuo and purification of the residue by flash chromatography on silicagel (5:4:1, hexanes:MDC:ether) gave 0.6 g (39%) of2-benzyl-4-isopropyl6-oxo-tetrahydro-Saccharin as a pale yellow foam.

The tetrahydrosaccharin (0.59 g, 1.7 mmol) was dissolved in toluene (50mi), dimethylamine hydrochloride (1.5 g, 18.0 mmol) and 4 A sieves (2.0g) were added. The resulting mixture was refluxed with azeotropicremoval of water for 96 hr. It was necessary to add additionaldimethylamine hydrochloride (0.8 g, 10.0 mmol) and 4 A sieves every 12hr during this 96 hr period at the end of which time, the reactionmixture was cooled to room temperature and filtered. The filter cake waswashed with diethyl ether (100 mi) and the combined filtrates wereconcentrated in vacuo to give 0.63 g (99% of2-benzyl4-isopropyl-6-dimethyl as a pale yellow solid.

To a solution of the dihydrosaccharin (0.63 g, 1.7 mmol) in refluxingchloroform (50 mi) was added activated manganese dioxide (4.3 g, 49.5mmol) in portions over a period of 4 hr, After the addition of the lastportion of manganese dioxide, the reaction was refluxed for anadditional hr, cooled to room temperature and filtered through a pad ofsuper cel, eluting with ethyl acetate. The combined eluents wereconcentrated in vacuo and the residue purified by flash chromatographyon silica gel (5:4:1, hexanes:MDC:ether) to give 0.32 g (50%) of2-benzyl-4-isopropyl-6-dimethylaminosaccharin as a colorless solid.

The 2-benzylsaccharin (0.32 g, 0.9 mmol) in methanol (20 mi) was treatedwith ammonium formate (0.24 g, 3.8 mmol) and 10% Pd on Carbon (0.25 g)and refluxed for 1 hr, cooled to room temperature and filtered through apad of super cel, eluting with methanol (100 mi). The combined eluentswere concentrated in vacuo. The residue was dissolved in MDC (10 mi),glacial acetic acid (0.25 mi) was added, stirred for 5 min. andevaporated to dryness in vacuo to give 0.25 g (100%) of4-isopropyl-6-dimethylamino-saccharin as a colorless foam.

Following a procedure similar to that described in Preparation 1, amixture of 4-isopropyl-6-dimethylaminosaccharin (0.27 g, 1.0 mmol),chloromethyl phenylsulfide (0.32 g, 2.0 mmol) and tetrabutyl ammoniumbromide (0.1 g, 0.2 mmol) in toluene was converted to 0.22 g (56%) of2-phenylthiomethyl-4-isopropyl-6-dimethylamino-saccharin which wastreated with sulfuryl chloride (1.86 mL of 0.31 M solution, 0.6 mmol) togive 0.15 g of a yellow gum that contained 25% (by NMR) of2-chloromethyl-4-isopropyl-6dimethylamino-7-chloro saccharin.

Preparation 28A

Thirty-one grams of 4-isopropyl-1,2-dimethoxybenzene was treated withN-bromosuccinimide followed by butyllithium and diethyl carbamylchloride as in preparation 6B 5to yield 15.2 g of2-isopropyl-4,5-dimethoxy-N,N-diethylbenzamide as a viscous oil. Thebenzamide was treated according to preparation 18B with butyllithium andsulfur dioxide followed by sulfuryl chloride then ammonia to provide 4.5g of the sulfonamide, mp 181-1820 from ether. This was cyclized inacetic acid as in preparation 18B to obtain 2.86 g of6,7-dimethoxy-4-isopropylsaccharin, mp 210°-212° from ethylacetate-hexane.

To a solution of 0.5 g of 4-isopropyl-6,7-dimethoxysaccharin in 3 mL ofDMF was added 0.5 mL of diisopropylethylamine at room temperature. After15 min, 0.35 g chloromethyl phenyl sulfide was added and the mixtureheated at 80° for 16 hrs. The reaction mixture was poured into EtOAc andwashed with aqueous Na₂ CO₃ solution, aqueous 2N HCl solution, saturatedaqueous NaCl solution. The organic layer was dried over Na₂ SO₄ and thesolvents removed. Chromatography with MDC gave 0.35 g of desiredproduct, which was used immediately. Treatment of the 0.35 g sample ofphenylthiomethyl saccharin in 3 mL of MDC with 0.1 mL of sulfurylchloride for 30 min at 20° followed by removal of solvents andtrituration with hexane gave 0.3 g of2-chloromethyl-6,7-dimethoxy-4-isopropylsaccharin.

Preparation 28B

To a solution of 5.7 g of methyl piperonylate in 20 mL of dry ether wasadded 30 mL of 3.0 methyl magnesium bromide in ether at 0° over 20 min,The mixture was stirred for 20 hrs then diluted with 200 mL of ether andwashed with water. The organic layer was dried with Na₂ SO₄ and thesolvents removed to yield 5.6 g of crude3,4-dimethoxy-(1'-hydroxy-1'-methylethyl)benzene. This material wasimmediately treated in 50 mL of acetic acid with 1 g of 10% Pd/C under50 psi of hydrogen for 20 hrs. Filtration to remove catalyst and removalof solvent yielded 4.5 g of 5-isopropyl-1,3-benzodioxole. Theisopropyldioxole was brominated, amidated, sulfonated and cyclized as in28A to yield 700 mg of 4-isopropyl-6,7-methylenedioxysaccharin, mp226°-228° from ethyl acetate/hexane. Five hundred milligrams of thesaccharin was chloromethylated as in 28A to provide 300 mg of2-chloromethyl-4-isopropyl-6,7-methylenedioxysaccharin, mp 174°-176°.

Other 4-R⁴ -R⁵ -saccharins of formula II useful as intermediates for thepreparation of the compounds of formula I can be prepared as follows.

Reaction of 2-trifluoromethylbenzoic acid with thionyl chloride affords2-trifluoromethylbenzoyl chloride, which, on reaction with diethylamine,affords 2-trifluoromethyl-N,N-diethylbenzamide. Following a proceduresimilar to that described in Preparation 5, reaction of the latter withs-butyl lithium and reaction of the resulting lithium salt with sulfurdioxide followed by sodium hydroxylamine-O-sulfonate affords2-trifluoromethyl-6-aminosulfonyl-N,N-diethylbenzamide, which, onheating in glacial acetic acid, affords 4-trifluoromethylsaccharin.

Similarly, reaction of 2-trichloromethylbenzoicacid with thionylchloride affords 2-trichloromethylbenzoylchloride, which, on reactionwith diethylamine, affords 2-trichloromethyl-N,N-diethylbenzamide.Following a procedure similar to that described in Preparation 5,reaction of the latter with s-butyl lithium and reaction of theresulting lithium salt with sulfur dioxide followed by sodiumhydroxyl-amine-O-sulfonate affords2-trichloromethyl-6-aminosulfonyl-N,N-diethylbenzamide, which, onheating in glacial acetic acid, affords 4-trichloromethylsaccharin.

Reaction of 4-cyclohexylbenzoic acid with thionylchloride affords4-cyclohexylbenzoyl chloride, which, on reaction with diethylamine,affords 4-cyclohexyl-N,N-diethyl-benzamide. Following a proceduresimilar to that described in Preparation 5, reaction of the latter withs-butyl lithium and reaction of the resulting lithium salt with sulfurdioxide followed by sodium hydroxylamine-O-sulfonate affords4-cyclohexyl-2-aminosulfonyl-N,N-diethylbenzamide, which, on heating inglacial acetic acid, affords 6-cyclohexyl saccharin.

Reaction of a 2-benzyl-6-aminosaccharin with methanesulfonyl chloride,trifluoromethylsulfonyl chloride or trichloro-methylsulfonyl chloride inMDC in the presence of pyridine followed by transfer hydrogenolysis ofthe 2-benzyl protecting group, affords, respectively,6-methylsulfonylaminosaccharin, 6-trifluoromethylsulfonylaminosaccharinor 6-trichloromethyl-sulfonylaminosaccharin.

Diazotization of 6-aminosaccharin with nitrous acid in an acid mediumand decomposition of the resulting diazonium salt in the presence ofcupric cyanide or cupric chloride and sulfur dioxide, or cupric chlorideand an alkali metal salt of methyl mercaptan or trifluoromethylmercaptan affords, respectively, 6-cyanosaccharin,6-chlorosulfonylsaccharin, 6-methylthiosaccharin or6-trifluoromethylthiosaccharin. Reaction of the6-chloro-sulfonylsaccharin in situ with ammonia or methanesulfonyl-amideaffords, respectively, 6-aminoslilfonylsaccharin and6-methanesulfonylaminosulfonylsaccharin. Oxidation of6-methylthiosaccharin and 6-trifluoromethylthiosaccharin with two molarequivalents of 3-chloroperbenzoic acid affords 6-methylsulfonylsaccharinand 6-trifluoromethylsulfonylsaccharin, respectively.

Hydrolysis of 6-cyanosaccharin by heating with aqueous sodium hydroxideaffords saccharin-6-carboxylic acid. Reaction of 6-cyanosaccharin byheating with a catalytic amount of sulfuric acid in ethanol solutionaffords ethyl saccharin-6-carboxylate, which, on reduction with lithiumborohydride, affords 6-hydroxymethylsaccharin. Oxidation of the latterwith pyridine:chromium trioxide (2:1) complex (Collins reagent) in MDCaffords 6-formylsaccharin, which, on reductive amination with ammoniaand sodium cyanoborohydride, affords 6-aminomethylsaccharin.

Reaction of 4-trifluoromethylbenzoic acid with thionyl chloride affords4-trifluoromethylbenzoyl chloride, which, on reaction with diethylamine,affords 4-trifluoromethyl-N,N-diethylbenzamide. Following a proceduresimilar to that described in Preparation 5, reaction of the latter withs-butyl lithium and reaction of the resulting lithium salt with sulfurdioxide followed by sodium hydroxylamine-O-sulfonate affords4-trifluoromethyl-2-aminosulfonyl-N,N-diethylbenzamide, which on heatingin glacial acetic acid, affords 6-trifluoromethylsaccharin.

Reaction of 4-trichloromethylbenzoic acid with thionyl chloride affords4-trichloromethylbenzoyl chloride, which, on reaction with diethylamine,affords 4-trichloromethyl-N,N-diethylbenzamide. Following a proceduresimilar to that described in Preparation 5, reaction of the latter withs-butyl lithium and reaction of the resulting lithium salt with sulfurdioxide followed by sodium hydroxylamine-O-sulfonate affords4-trichloromethyl-2-aminosulfonyl-N,N-diethylbenzamide, which, onheating in glacial acetic acid, affords 6-trichloromethylsaccharin.

Reaction of 2-ethenylbenzoic acid with thionyl chloride affords2-ethenylbenzoyl chloride, which on reaction with diethylamine, affords2-ethenyl-N,Ndiethylbenzamide. Reaction of the latter with s-butyllithium and reaction of the resulting lithium salt with sulfur dioxidefollowed by sodium hydroxylamine-O-sulfonate affords2-ethenyl-6-aminosulfonyl-N,N-diethylbenzamide, which, on heating inglacial acetic acid, affords 4-ethenylsaccharin.

Reaction of 2-ethenyl-6-aminosulfonyl-N,N-diethylbenzamide with bromineaffords 2-(1,2-dibromoethyl)-6-aminosulfonyl-N,N-diethylbenzamide which,on reaction with sodium amide in ammonia affords2-ethynyl-6-aminosulfonyl-N,N-diethylbenzamide, which, on heating inglacial acetic acid, affords 4-ethynylsaccharin.

Reaction of ethyl 2-aminobenzoate with two molar equivalents of benzylchloride in acetone in the presence of potassium carbonate affords ethyl2-(N,N-dibenzylamino)benzoate which, on saponification in aqueousethanolic potassium hydroxide and isolation of the product from aneutral medium, affords 2-(N,N-dibenzylamino)benzoic acid,

Reaction of the latter with thionyl chloride affords2-(N,N-dibenzylamino)benzoyl chloride, which, on reaction withdiethylamine, affords 2-(N,N-dibenzylamino)N,N-diethyl-benzamide.Reaction of the latter with s-butyl lithium and reaction of theresulting lithium salt with sulfur dioxide followed by sodiumhydroxylamine-O-sulfonate affords2-(N,N-dibenzyl)-6-aminosulfonyl-N,N-diethyl-benzamide, which, onheating in glacial acetic acid, affords 4-(N,N-dibenzyl-amino)saccharinwhich, on catalytic debenzylation with hydrogen overpalladium-on-charcoal, affords 4-amino-saccharin. Reductive alkylationof the latter with one molar equivalent of formaldehyde in formic acidaffords 4-methylaminosaccharin.

Reaction of 4-isopropyl-6-hydroxysaccharin (Preparation 19) withN,N-diethylthiocarbamyl chloride in DMF using the procedure describedabove in Preparation 12 affords4-isopropyl-6-(N,N-diethylthiocarbamyloxy)saccharin which, on heating,rearranges to 4-isopropyl-6-(N,N-diethylcarbamyl-thio)saccharin. Thelatter, on hydrolysis with alkali, affords4-isopropyl-6-mercaptosaccharin which, after benzylation, reaction withmethyl iodide, and transfer hydrogenolysis affords4-isopropyl-6-methylthiosaccharin. Oxidation of the latter with one ortwo molar equivalents of 3-chloroperbenzoic acid affords4-isopropyl-6-methylsulfinylsaccharin and4-isopropyl-6-methylsulfonylsaccharin.

Reaction of 2-isopropyl-4-fluorobenzoic acid with thionyl chlorideaffords 2-isopropyl-4-fluorobenzoylchloride, which, on reaction withdiethylamine, affords 2-isopropyl- 4-fluoro-N,N-diethylbenzamide.Reaction of the latter with s-butyl lithium and reaction of theresulting lithium salt with sulfur dioxide followed by sodiumhydroxylamine-O-sulfonate affords2-isopropyl-4-fluoro-6-aminosulfonyl-N,N-diethylbenzamide, which, onheating in glacial acetic acid, affords 4-isopropyl-6-fluorosaccharin.

Reaction of the latter with thiophenol, 4-methylphenylthiophenol,4-methoxyphenylthiophenol, 4-chlorophenylthiophenol,1-mercapto-4-methylnaphthalene or 1-mercaptonaphthalene by heating thereactants in DMF affords, respectively,4-isopropyl-6-phenylthiosaccharin,4-isopropyl-6-(4-methylphenylthio)saccharin,4-isopropyl-6-(4-methoxyphenylthio)saccharin,4-isopropyl-6-(4-chloro-phenylthio)saccharin,4-isopropyl-6-(4-methyl-1-naphthylthio)saccharin,4-isopropyl-6-(4-methyl-1-naphthylthio)saccharin and4-isopropyl-6-(1-naphthylthio)saccharin. Oxidation of the latter withone or two molar equivalents of 3-chloroperbenzoic acid affords4-isopropyl-6-phenylsulfinylsaccharin,4-isopropyl-6-pehnylsulfonylsaccharin,4-isopropyl-6-(4-methylphenylsulfinyl)saccharin,4-isopropyl-6-(4-methylphenylsufonyl)saccharin,4-isopropyl-6-(4-methoxyphenylsulfinyl)saccharin,4-isopropyl-6-(4-methoxyphenylsulfonyl)saccharin,4-iso-propyl-6-(4-chlorophenylsulfinyl)saccharin,4-isopropyl-6-(4-chlorophenylsulfonyl)saccharin,4-isopropyl-6-(4-methyl-1-naphthylsulfinyl)saccharin,4-isopropyl-6-(4-methyl-1-naphthylsulfonyl)saccharin,4-isopropyl-6-(1naphthylsulfinyl)saccharin and4-isopropyl-6-(1-naphthylsulfonyl)saccharin.

Reaction of 4-isopropyl-6-hydroxysaccharin (Preparation 19) with onemolar equivalent of acetic anhydride, benzoyl chloride or 1-naphthylcarboxylic acid chloride affords, respectively,4-isopropyl-6-acetoxysaccharin, 4-isopropyl-6-benzoyloxysaccharin and4-isopropyl-6-(1-naphthylcarbonyloxy)saccharin.

Heating 4-isopropyl-6-fluorosaccharin in DMF with azetidine,pyrrolidine, piperidine, morpholine, 1-benzylpiperazine,1-methylpiperazine, imidazole, t-butyl alphaamino-acetate or ammoniaaffords, respectively, 4-isopropyl6(1-azetidinyl)saccharin,4-isopropyl-6-(1-pyrrolidinyl)saccharin,4-isopropyl-6-(1-piperidinyl)saccharin,4-isopropyl-6-(4-morpholinyl)saccharin,4-isopropyl-6-(4-benzyl-1-piperazinyl)saccharin,4-isopropyl-6-(4-methyl-1-piperazinyl)saccharin,4-isopropyl-6-(1-1H-imidazolyl)-saccharin,4-isopropyl-6-(carbo-t-butoxymethylamino)saccharin and4-isopropyl-6-aminosaccharin.

Catalytic debenzylation of4-isopropyl-6-(4-benzyl-1-piperazinyl)saccharin with hydrogen overpalladium on charcoal affords 4-isopropyl-6-(1-piperazinyl)saccharin.

Hydrolysis of 4-isopropyl-6-(carbo-t-butoxycarbonylmethylamino)saccharinwith dilute hydrochloric acid and isolation of the product from aneutral medium affords 4-isopropyl-6-carboxymethylaminosaccharin.

Reaction of 4-isopropyl-6-aminosaccharin with one molar equivalent ofacetyl chloride affords 4-isopropyl-6-acetylaminosaccharin.

Saponification of 4-carbomethoxysaccharin (Preparation 9D) to thecorresponding saccharin-4-carboxylic acid by alkaline hydrolysis,conversion of the acid to the corresponding acid chloride by reaction ofthe acid with thionyl chloride and reaction of the acid chloride withammonia affords saccharin-4-carboxamide.

Reaction of each of the 4-R⁴ -R⁵ -saccharins soprepared withparaformaldehyde and chlorotrimethylsilane in the presence of stannicchloride in ethylene dichloride affords the 4-R⁴ -R⁵-2-chloro-methylsaccharins of formula IV listed in TABLE B where, ineach instance, X is Cl.

                  TABLE B                                                         ______________________________________                                        Preparation                                                                              R.sup.4     R.sup.5                                                ______________________________________                                        19A        CF.sub.3    H                                                      19B        CCl.sub.3   H                                                      19C        H           6-cyclohexyl                                           19D        H           6-CH.sub.3 SO.sub.2 NH                                 19E        H           6-CF.sub.3 SO.sub.2 NH                                 19F        H           6-CCl.sub.3 SO.sub.2 NH                                19G        H           6-CN                                                   19H        H           6-NH.sub.2 SO.sub.2                                    19I        H           6-CH.sub.3 SO.sub.2 NHSO.sub.2                         19J        H           6-CH.sub.3 SO.sub.2                                    19K        H           6-CF.sub.3 SO.sub.2                                    19L        H           6-HOOC                                                 19M        H           6-HOCH.sub.2                                           19N        H           6-OHC                                                  19-O       H           6-NH.sub.2 CH.sub.2                                    19P        H           6-CF.sub.3                                             19Q        H           6-CCl.sub.3                                            19R        CH═CH.sub.2                                                                           H                                                      19S        C.tbd.CH    H                                                      19T        NH.sub.2    H                                                      19U        CH.sub.3 NH H                                                      19V        (CH.sub.3).sub.2 N                                                                        H                                                      19W        CH(CH.sub.3).sub.2                                                                        6-CH.sub.3 S                                           19X        CH(CH.sub.3).sub.2                                                                        6-CH.sub.3 SO                                          19Y        CH(CH.sub.3).sub.2                                                                        6-CH.sub.3 SO.sub.2                                    19Z        CH(CH.sub.3).sub.2                                                                        6-F                                                    19AA       CH(CH.sub.3).sub.2                                                                        6-C.sub.6 H.sub.5 S                                    19AB       CH(CH.sub.3).sub.2                                                                        6-(4-CH.sub.3 C.sub.6 H.sub.4 S)                       19AC       CH(CH.sub.3).sub.2                                                                        6-(4-CH.sub.3 OC.sub.6 H.sub.4 S)                      19AD       CH(CH.sub.3).sub.2                                                                        6-(4-ClC.sub.6 H.sub.4 S)                              19AE       CH(CH.sub.3).sub.2                                                                        6-(4-CH.sub.3 -1-naphthyl-S)                           19AF       CH(CH.sub.3).sub.2                                                                        6-(1-naphthyl-S)                                       19AG       CH(CH.sub.3).sub.2                                                                        6-C.sub.6 H.sub.5 SO                                   19AH       CH(CH.sub.3).sub.2                                                                        6-C.sub.6 H.sub.5 SO.sub.2                             19AI       CH(CH.sub.3).sub.2                                                                        6-(4-CH.sub.3 C.sub.6 H.sub.4 SO)                      19AJ       CH(CH.sub.3).sub.2                                                                        6-(4-CH.sub.3 C.sub.6 H.sub.4 SO.sub.2)                19AK       CH(CH.sub.3).sub.2                                                                        6-(4-CH.sub.3 OC.sub.6 H.sub.4 SO)                     19AL       CH(CH.sub.3).sub.2                                                                        6-(4-CH.sub.3 OC.sub.6 H.sub.4 SO.sub.2)               19AM       CH(CH.sub.3).sub.2                                                                        6-(4-ClC.sub.6 H.sub.4 SO)                             19AN       CH(CH.sub.3).sub.2                                                                        6-(4-ClC.sub.6 H.sub.4 SO.sub.2)                       19AO       CH(CH.sub.3).sub.2                                                                        6-(4-CH.sub.3 -1-naphthyl-SO)                          19AP       CH(CH.sub.3).sub.2                                                                        6-(4-CH.sub.3 -1-naphthyl-SO.sub.2)                    19AQ       CH(CH.sub.3).sub.2                                                                        6-(1-naphthyl-SO)                                      19AR       CH(CH.sub.3).sub.2                                                                        6-(1-naphthyl-SO.sub.2)                                19AS       CH(CH.sub.3).sub.2                                                                        6-CH.sub.3 COO                                         19AT       CH(CH.sub.3).sub.2                                                                        6-C.sub.6 H.sub.5 COO                                  19AU       CH(CH.sub.3).sub.2                                                                        6-(1-naphthyl-COO)                                     19AV       CH(CH.sub.3).sub.2                                                                        6-(1-azetidinyl)                                       19AW       CH(CH.sub.3).sub.2                                                                        6-(1-pyrrolidinyl)                                     19AX       CH(CH.sub.3).sub.2                                                                        6-(1-piperidinyl)                                      19AY       CH(CH.sub.3).sub.2                                                                        6-(4-morpholinyl)                                      19AZ       CH(CH.sub.3).sub.2                                                                        6-(4-benzyl-1-piperazinyl)                             19BA       CH(CH.sub.3).sub.2                                                                        6-(4-methyl-1-piperazinyl)                             19BB       CH(CH.sub.3).sub.2                                                                        6-(1-1H-imidazolyl)                                    19BC       CH(CH.sub.3).sub.2                                                                        6-(NHCH.sub.2 COOC.sub.4 H.sub.9 -t)                   19BD       CH(CH.sub.3).sub.2                                                                        6-NH.sub.2                                             19BE       CH(CH.sub.3).sub.2                                                                        6-(1-piperazinyl)                                      19BF       CH(CH.sub.3).sub.2                                                                        6-(NHCH.sub.2 COOH)                                    19BG       CH(CH.sub.3).sub.2                                                                        6-(CH.sub.3 CONH)                                      19BH       CONH.sub.2  H                                                      ______________________________________                                    

Preparation 19BI

Reaction of isothiazole-5-carboxaldehyde with lithium3-(triphenylphosphoranylidene)propanoate under standard Wittigconditions provides 4-(5-isothiazolyl)-3-butenoic acid which is reducedand cyclized with aluminum chloride to provide4-oxo-4,5,6,7-tetrahydrobenzisothiazole. The 4-oxo compound is reactedwith methylenetriphenyl phosphorane under standard Wittig conditions anda methylene is inserted into the resulting 4-methylene compound via aSimmons Smith reaction to provide6,7dihydrospiro[benzisothiazol-4(5H),1'-cyclopropane] which is oxidizedwith hydrogen peroxide in acetic acid to give6,7-dihydrospiro[benzisothiazol-4(5H), 1'-cyclopropane 1,1-dioxide(4-spiro-cyclopropyl tetrahydrosaccharin). This is chloromethylatedaccording to the procedure of Preparation 1A to give2-chloromethyl-4-spirocyclopropyl-4,5,6,7-tetrahydrosaccharin.

Preparation 19BJ

2-Benzyl-4-isopropyl-6-oxo-tetrahydrosaccharin of preparation 23 isreduced with sodium borohydride and methylated with methyl iodide in thepresence of sodium hydride to provide2-benzyl-4-isopropyl-6-methoxy-tetrahydrosaccharin. This is debenzylatedand chloromethylated as in preparation 23 to provide2-chloromethyl-4-isopropyl-6-methoxy-4,5,6,7-tetrahydrosaccharin.

Preparation 20A

A mixture of 10.0 g (0.063 mol) of 2,6-difluorobenzoic acid and 66.0 g(0.57 mol) of chlorosulfonic acid was heated at 155°-160° C. and thenpoured carefully into 100 ml of ice water. The solids which separatedwere collected by filtration, air dried and recrystallized fromchloroform to give 7.0 g of 3-chlorosulfonyl-2,6-difluorobenzoic acid,0.64 g (0.0025 mol) of which was dissolved in MDC and treated at -10° C.with a solution of 0.25 g (0.0025 mol) of 1-methyl-piperazine and 0.33 g(0.0026 mol) of diisopropylethylamine. The product which separated wascollected by filtration, washed with MDC and dried to give 0.4 g (50%)of 2,6-difluoro-3-(4-methyl-1-piperazinyl)sulfonylbenzoic acid.

Preparations 20B-20G

Following a procedure similar to that described in Preparation 20Aabove, 3-chlorosulfonyl-2,6-dichlorobenzoic acid, m.p, 172°-175° C.(from chloroform) was prepared in 56% yield by heating a mixture of2,6-dichlorobenzoic acid with chlorosulfonic acid at 150°-160° C.

Reaction of the latter with an appropriate amine (N=B) afforded the3-aminosulfonyl-2,6-dichlorobenzoic acids listed in TABLE C below. Ineach instance products were not further purified but were used as suchin the next step.

                  TABLE C                                                         ______________________________________                                        Preparation N═B          Yield                                            ______________________________________                                        20B         4-morpholinyl    86                                               20C         NHCH.sub.2 COO--C.sub.4 H.sub.9 -(t)                                                           36                                               20D         4-CH.sub.3 -1-piperazinyl                                                                      40                                               20E         4-C.sub.6 H.sub.5 CH.sub.2 -1-piperazinyl                                                      59                                               20F         N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                 82                                               20G         NHCH.sub.2 COOBzl                                                                              50                                               ______________________________________                                    

To a mixture of 1.0 g (0.003 mol) of benzyl2,6-dichloro-3-hydroxybenzoate and 0.18 g of 60% dispersion of sodiumhydride in mineral oil in 30 ml of DMF was added a solution of 0.008 molof 4-(2-chloroethyl)morpholine in 20 ml of t-butyl methyl ether and themixture heated at 70° C. for three hours. The reaction mixture was thentaken to dryness and the residue taken up in ethyl acetate and theorganic solution washed with water and brine, then dried andconcentrated in vacuo to dryness to give 1.25 g (83%) of benzyl2,6-dichloro-3-[2-(4-morpholinyl)ethoxy]benzoate which was dissolved in1:1 ethyl acetate:methanol (50 ml) and reduced with hydrogen over 0.25 gof 10% palladium-oncharcoal. When reduction was complete, the catalystwas removed by filtration, washed with DMF and the combined filtratestaken to dryness in vacuo to give 0.75 g (75%) of2,6-dichloro-3-[2-(4-morpholinyl)ethoxy]benzoic acid.

Preparation 21B

Following a procedure similar to that described in Preparation 21A, 1.0q (0.003 mol) of benzyl 2,6-dichloro-3-hydroxybenzoate was reacted with0.092 mol of N-(2-chloroethyl)-N,N-dimethylamine in 30 ml of DMF and 20ml of t-butyl methyl ether in the presence of 0.18 g of a 60% mineraloil dispersion of sodium hydride to give a quantitative yield of benzyl2,6-dichloro-3-[2-(dimethylamino)ethoxy]benzoate which was reducedcatalytically in a 5:2 solution of ethyl acetate:methanol over 0.2 g of10% palladium-on-charcoal. There was thus obtained 0.2 g (22%) of2,6-dichloro-3-[2-(dimethylamino)ethoxy]benzoic acid.

Preparation 21C

To a solution of methyl 2,6-dichloro-4-methoxybenzoate (J. Org. Chem.,50, 408 1985) (5.5 g, 0.023 mol) in methanol (50 mi) was added 5N sodiumhydroxide (20 mL). The resulting mixture was heated at reflux for 20 hr,cooled to room temperature, concentrated in vacuo and acidified to pH 1with 2N HCI. The separated solids were collected by filtration to give5.2 g (100%) of 2.6-dichloro-4-methoxybenzoic acid, which was treatedwith 60 mL of a 1M solution of boron tribromide (0.06 mol) indichloroethane (100 mi) at reflux for 2 hr. The resulting mixture wascooled to room temperature and poured onto water/reethanol (50 mL of a9:1 mixture). After stirring for 10 minutes, the mixture was extractedwith ether (400 mL) and the organic phase washed with water, brine anddried. Removal of the solvent in vacuo gave 4.0 g (80%) of2,6-dichloro-4-hydroxyhenzoic acid.

The latter (1.05 g, 0.005 mol) was dissolved in 595% ethanol (25 mi) andtreated with benzyl chloride (0.71 g, 0.006 mol) and 1N NAOH (5 mi).After refluxing under nitrogen for 2 hr, the reaction mixture was cooledto room temperature and concentrated in vacuo. The residue was acidifiedwith 2N HCl and extracted with ether. The organic phase was washed withsaturated NaHCO₃, water and 10% NAOH. After discarding the organicphase, the NAOH washings were acidified with 2N HCl and reextracted withether (2×50 mL). The ether extract was then dried and concentrated invacuo to give 0.63 g (42%) of benzyl-2,6-dichloro-4-hydroxybenzoate.

Following a procedure similar to that described in Preparation 21A, 630mg of benzyl 2,6-dichloro-4-hydroxybenzoate was converted to 350 mg of2,6-dichloro-4[2-(4-morpholinyl)ethoxy]benzoic acid.

Preparation 24A

A solution of 1.9 g (0.01 mol) of 2,6-dichloro-3-hydroxybenzaldehyde in10 mL dry DMF was flushed with nitrogen and 0.3 g of 97% sodium hydridewas added with magnetic stirring. Hydrogen was evolved giving a clearred-brown solution. To this was added a solution of2-dimethylaminoethylchloride (from 2.0 g of the hydrochloride) in 6 mLof t-butylmethyl ether. The solution was heated to reflux for 1/2 hr.Sodium chloride precipitated. The condenser was removed and heating wascontinued for 1/2 hr. The reaction mixture was concentrated to dryness,taken up in dilute HCl and extracted with methylene chloride. Theaqueous layer was basified with 10% Na₂ CO₃ solution, extracted 3× withCH₂ Cl₂ and the extracts evaporated to a brown oil which was distilledin a Kugelrohr, bp 155°-160°/0.12 mm. The yellow distillate crystallizedand was converted to the hydrochloride with ethereal HCl.Recrystallization from CH₃ CN gave 661 mg of2,6-dichloro-3-[2-dimethylamino)ethoxy]benzaldehyde hydrochloride, mp177°-178°.

Freshly prepared silver oxide (from 1.7 g AgNO₃) was suspended in 1.0 mLof 10% sodium hydroxide solution which was then heated to 55°. Thealdehyde (2.62 g, 0.01 mm) was added with magnetic stirring. Theexothermic reaction raised the temperature to 65° and silverprecipitated. Heating was continued at 60° for 1/4 hr. The reaction wasfiltered and the filtrate extracted 2× with CH₂ Cl₂. Evaporation of theCH₂ Cl₂ gave 0.804 g of starting aldehyde. The aqueous phase wasacidified with 3N HCl and evaporated in vacuo to a white solid which wasrecrystallized from 10 mL of water. There was obtained 1.065 g (34%) of2,6-dichloro-3-[2-(dimethylamino)ethoxy]benzoic acid, mp 234°-236°.

Preparations 24B-24D

Following a procedure similar to that described in Preparation 24Aabove, the aldehydes and acids shown in Table D were prepared:

                  TABLE D                                                         ______________________________________                                        Prep-                              Acid HCl Salt                              aration                                                                             N═B     bp          yield                                                                              mp     yield                               ______________________________________                                        24B   2-(1-pyrro- 130-140/0.1 mm                                                                            41   253-255                                                                              10                                        lidinyl)-                                                                     ethoxy                                                                  24C   2-(1-piper- 160-180/0.1 mm                                                                            54   241-242                                                                              24                                        dinyl) ethoxy                                                           24D   2-(diethyl- not distilled                                                                             --   220-222                                                                              15                                        amino) ethoxy                                                           ______________________________________                                    

Preparation 25

To a solution of chlorine (15.7 g, 0.22 mol) in glacial acetic acid (250mi) at 0° C. was added methyl 3-hydroxybenzoate (15.2g, 0.1 mol). Theresulting solution was warmed to room temperature and stirred for 1 hrand evaporated to dryness in vacuo to give 21.4 g of a yellow oil whichwas found to contain 75% of methyl 2,6-dichloro-3-hydroxybenzoate byNMR. The oil (21.4 g) was dissolved in acetone (600 mL), benzyl bromide19.9 g, 0.12 mol) and potassium carbonate (22.7 g, 0.16 mol) were addedand refluxed under nitrogen for 16 hr. The reaction mixture was cooledto room temperature and the solids filtered off. The filtrate wasconcentrated in vacuo and the residue taken up in 10% ethyl acetate inhexanes (100 mL) and chilled in an ice bath. The solids that emergedwere collected by filtration and air dried to give 14.3 g (47%) ofmethyl 2,6-dichloro-3-benzyloxybenzoate.

A solution of methyl 2,6-dichloro-3-benzyloxybenzoate (2.1 g, 6.7 mmol)and 10% aqueous NAOH (25 mL) in methanol (25 mL) was refluxed undernitrogen for 24 hr and cooled to room temperature. The resulting mixturewas concentrated to one-half the volume in vacuo and acidified to pH 1with 2N HCl. the solids that precipitated were collected by filtration,washed with water, hexanes and air dried to give 2.0 g (100%) of2,6-dichloro-3-benzyloxybenzoic acid as a white solid.

Preparation 26

A solution of 5 g of 2,6-dimethoxy-3-nitrobenzoic acid in THF washydrogenated in the presence of 10% Pd on C and the resulting amine wasacetylated in situ with acetic anhydride and pyridine to provide 0.9 gof 3-acetylamino-2,6-dimethoxybenzoic acid.

Preparation 27

To a suspension of 3.6 g (0.12 mol) of paraformaldehyde in 50 mL of1,2-dichloroethane and 30 mL (26 g, 0.24 mol) of trimethylsilyl chlorideunder nitrogen was added 0.2 mL of stannic chloride and the resultingsolution was stirred on a steam bath. After 30 min, 9.55 g (0.05 mol) of2,6-dichlorobenzoic acid was added and the reaction heated for anadditional 20 hours. Volatiles were removed, the residue dissolved inMDC and washed with NaHCO₃, dried and stripped to an oil which wastriturated in hexane and filtered to obtain 8.5 g ofchloromethyl-2,6-dichlorobenzoate.

Preparation of the Final Products EXAMPLE 1A

A mixture of 0.5 g (0.0017 mol) of2-chloromethyl-4,6-dimethoxysaccharin, 0.33 g (0.0017 mol) of2,6-dichlorobenzoic acid and 17 g (0.25 ml, 0.0017 mol) of triethylaminein 15 ml of toluene was heated under reflux for about six hours, thencooled and concentrated to dryness in vacuo. The residue waschromatographed on silica gel, eluting with 40% ethyl acetate/hexane togive 0.44 g (53%) of 4,6-dimethoxy-2-saccharinylmethyl2,6-dichlorobenzoate, m.p. 200°-201° C.

Following a procedure similar to that described in Example 1A above, thecompounds of formula I listed in TABLE 1 below were similarly prepared.The reactions were carried out either in the presence of cesiumcarbonate, potassium carbonate, triethylamine (TEA),diisopropylethylamine (DIPEA), or 1,8-diazabicyclo-[5.4.0]undec-7-ene(DBU) as basic catalyst or by use of the cesium or thallium salt of thebenzoic acid and optionally in the presence of tetrabutylammoniumbromide (TBAB) in an appropriate organic solvent as indicated in thecolumn headed "Solv./Cat". NMP is N-methylpyrrolidinone. In each ofExamples 1D-1I, IN, IAI and 1AJ-1AN the products were prepared from the4-R⁴ -R⁵ -2-bromomethylsaccharin. In all other examples the appropriate4-R⁴ -R⁵ -2-chloromethylsaccharin was used as the starting material.Here and elsewhere in this specification various heterocyclic or othergroups are abbreviated as follows:

    ______________________________________                                        Ac                  acetyl                                                    Mor                 morpholinyl                                               pip                 piperazinyl                                               Bzl                 benzyl                                                    azet                azetidinyl                                                imidazol            imidazolyl                                                pyr                 pyrrolidinyl                                              pid                 piperidinyl                                               ______________________________________                                    

                                      TABLE 1                                     __________________________________________________________________________    Ex R.sup.4 /R.sup.5                                                                       Ar                    Solv/Cat                                                                              m.p./Solv Yield                     __________________________________________________________________________    1B CH(CH.sub.3).sub.2                                                                     2,6-Cl.sub.2 C.sub.6 H.sub.3                                                                        DMF     Foam      77                           6-CH.sub.3 O                   K.sub.2 CO.sub.3 /TBAB                      1C CH(CH.sub.3).sub.2                                                                     2,6-Cl.sub.2 C.sub.6 H.sub.3                                                                        DMF     130-131   67                           6-HO                           Cs.sub.2 CO.sub.3                           1D H        2,6-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3                                                              acetone 155-156   26                           H                              K.sub.2 CO.sub.3                                                                      i-PrOAc                             1E H        2,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3                                                              CH.sub.3 CN                                                                           147-148   67                           H                              DBU     CH.sub.3 CN                         1F H        1-naphthyl            xylene  161-163   55                           H                              TEA     CH.sub.3 CN                         1G H        2-Cl-6-AcNHC.sub.6 H.sub.3                                                                          xylene  164-165   49                           H                              TEA     CH.sub.3 CN                         1H H        2,6-Br.sub.2 C.sub.6 H.sub.3                                                                        xylene  196-197   56                           H                              TEA     CH.sub.3 CN                         1I CH(CH.sub.3).sub.2                                                                     1-naphthyl            xylene  146-148   56                           H                              TEA     CH.sub.3 CN                         1J H        2,6-F.sub.2 C.sub.6 H.sub.3                                                                         DMF     113-115   42                           H                              Cs.sub.2 CO.sub.3                           1K CH(CH.sub.3).sub.2                                                                     2,6-(CH.sub.3).sub.2 C.sub.6 H.sub.3                                                                DMF/CH.sub.3 OH                                                                       80-81     18                           H                              Cs.sub.2 CO.sub.3                           1L CH(CH.sub.3).sub.2                                                                     9-anthryl             toluene 184-185   46                           H                              TEA                                         1M CH(CH.sub.3).sub.2                                                                     2,5-Cl.sub.2 C.sub.6 H.sub.3                                                                        DMF/CH.sub.3 OH                                                                       125-126   66                           H                              Cs.sub.2 CO.sub.3                           1N H        C.sub.6 H.sub.5       DMF     108-110   21                           H                              Tl salt i-PrOH                              1-O                                                                              CH.sub.3 2,6-Cl.sub.2 C.sub.6 H.sub.3                                                                        DMF     167-168   87                           H                              Tl salt/TBAB                                1P C.sub.2 H.sub.5                                                                        2,6-Cl.sub.2 C.sub.6 H.sub.3                                                                        DMF     113-115   83                           H                              Tl salt/TBAB                                1Q CH(CH.sub.3).sub.2                                                                     2,6-Cl.sub.2 C.sub.6 H.sub.3                                                                        DMF     119-120   83                           H                              Tl salt/TBAB                                1R C.sub.6 H.sub.5                                                                        2,6-Cl.sub.2 C.sub.6 H.sub.3                                                                        DMF     144-146   80                           H                              Tl salt/TBAB                                1S H        2,6-Cl.sub.2 -3-(SO.sub.2 -Mor)C.sub.6 H.sub.2                                                      DMF     148-150   38                           H                              Tl salt/TBAB                                1T H        2,6-Cl.sub.2 -3-(SO.sub.2 NHCH.sub.2 COOH)C.sub.6 H.sub.2                                           acetone 205-207   54                           H                              K.sub.2 CO.sub.3                            1U CH(CH.sub.3).sub.2                                                                     2,6-Cl.sub.2 -3-(SO.sub.2 -4-Mor)C.sub.6 H.sub.2                                                    acetone 139-141   81                           H                              K.sub.2 CO.sub.3 /TBAB                      1V CH(CH.sub.3).sub.2                                                                     2,6-Cl.sub.2 -3-(SO.sub.2 -4-CH.sub.3 -1-pip)C.sub.6 H.sub.2                                        DMF     >180.sup.(b)                                                                            94                           H                              K.sub.2 CO.sub.3 /TBAB                      1W CH(CH.sub.3).sub.2                                                                     2,6-Cl-3-(SO.sub.2 NHCH.sub.2 COOH)C.sub.6 H.sub.2                                                  DMF     >180.sup.(c)                                                                             8                           H                              K.sub.2 CO.sub.3 /TBAB                      1X CH(CH.sub.3).sub.2                                                                     3-BzlOC.sub.6 H.sub.4.sup.(d)                                                                       DMF     65-68     16                           H                              K.sub.2 CO.sub.3 /TBAB                      1Y CH(CH.sub.3).sub.2                                                                     2,6-Cl.sub.2 -3-BzlOC.sub.6 H.sub.2.sup.(d)                                                         DMF     80-83     12                           H                              K.sub.2 CO.sub.3 /TBAB                      1Z CH(CH.sub.3).sub.2                                                                     2,6-Cl.sub.2 -3-(SO.sub.2 -4-Bzl-1-pip)C.sub.6 H.sub.2                                              DMF     172-175.sup.(b)                                                                         75                           H                              K.sub.2 CO.sub.3 /TBAB                      1AA                                                                              CH(CH.sub.3).sub.2                                                                     2,6-Cl.sub.2 -3-[SO.sub.2 N(CH.sub.3)CH.sub.2 CH.sub.2                        N(CH.sub.3).sub.2 ]C.sub.6 H.sub.2                                                                  DMF     128-133.sup.(b)                                                                         62                           H                              K.sub.2 CO.sub.3 /TBAB                      1AB                                                                              CH(CH.sub.3).sub.2                                                                     2,6-Cl.sub.2 -3-CH.sub. 3 OC.sub.6 H.sub.2                                                          DMF     166-168   46                           H                              K.sub.2 CO.sub.3 /TBAB                      1AC                                                                              CH(CH.sub.3).sub.2                                                                     2,6-Cl.sub.2 -4-CH.sub.3 OC.sub.6 H.sub.2                                                           DMF     178-180   74                           H                              K.sub.2 CO.sub.3 /TBAB                      1AD                                                                              CH(CH.sub.3).sub.2                                                                     2,6-Cl.sub.2 -3-(OCH.sub.2 CH.sub.2 -4-Mor)C.sub.6 H.sub.2                                          DMF     140-143.sup.(b)                                                                         90                           H                              K.sub.2 CO.sub.3 /TBAB                      1AE                                                                              CH(CH.sub.3).sub.2                                                                     2,6-Cl.sub.2 -3-[OCH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                         ]C.sub.6 H.sub.2      DMF     135-138.sup.(b)                                                                         74                           H                              K.sub.2 CO.sub.3 /TBAB                      1AF                                                                              CH(CH.sub.3).sub.2                                                                     2,6-Cl.sub.2 -2-[SO.sub.2 N(CH.sub.3)(CH.sub.2).sub.3                         N(CH.sub.3).sub.2 ]C.sub.6 H.sub.2                                                                  DMF     143-148.sup.(e)                                                                         93                           H                              K.sub.2 CO.sub.3 /TBAB                      1AG                                                                              CH(CH.sub.3).sub.2                                                                     2,6-F.sub.2 -3-[SO.sub.2 -(4-CH.sub.3 -1-pip)]C.sub.6                                               DMFub.2 >161.sup.(f)                                                                            95                           H                              K.sub.2 CO.sub.3 /TBAB                      1AH                                                                              CHCH.sub.3 C.sub.2 H.sub.5                                                             2,6-Cl.sub.2 C.sub.6 H.sub.3                                                                        DMF     110-113   26                           H                              K.sub.2 CO.sub.3 /TBAB                      1AI                                                                              H        2,6-Cl.sub. 2 C.sub.6 H.sub.3                                                                       DMF     158-159   31                           H                              Tl salt i-PrOH                              1AJ                                                                              H        2,6-F.sub.2 C.sub.6 H.sub.3                                                                         EtOH    126-127   28                           H                              Tl salt i-PrOH                              1AK                                                                              H        2,6-(CH.sub.3).sub.2 C.sub.6 H.sub.3                                                                EtOH    138-140   29                           H                              Tl salt i-PrOH                              1AL                                                                              H        2,3,6-Cl.sub.3 C.sub.6 H.sub.2                                                                      EtOH    174-176   33                           H                              Tl salt i-PrOH                              1AM                                                                              H        9-anthryl             xylene  208-210   52                           H                              TEA     CH.sub.3 CN                         1AN                                                                              H        2,6-(CF.sub.3).sub.2 C.sub.6 H.sub.3                                                                DMF     153-155   49                           H                              Tl salt                                     1AO                                                                              CH(CH.sub.3).sub.2                                                                     2,4-Cl.sub.2 C.sub.6 H.sub.3                                                                        DMF       130-131.5                                                                             62                           H                              K.sub.2 CO.sub.3 /TBAB                      1AP                                                                              CH(CH.sub.3).sub.2                                                                     2,6-Cl.sub.2 -3-[SO.sub.2 -(4-CH.sub.3 -1-pip)]C.sub.6                        H.sub.2               DMF     151.sup.(b)                                                                             65                           6-CH.sub.3 O                   K.sub.2 CO.sub.3 /TBAB                      1AQ                                                                              CH(CH.sub.3).sub.2                                                                     2,6-Cl.sub.2 -3-[SO.sub.2 N(CH.sub.3)CH.sub.2 CH.sub.2                        N(CH.sub.3).sub.2 ]   DMF     145-155.sup.(b)                                                                         23                           6-CH.sub.3 O                   K.sub.2 CO.sub.3 /TBAB                      1AR                                                                              CH(CH.sub.3 ).sub.2                                                                    2,6-Cl.sub.2 -3-      DMF     151.sup.(b)                                                                             38                           6-CH.sub.3 O                                                                           [SO.sub.2 N(CH.sub.3)CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                      ]-C.sub.6 H.sub.2     K.sub.2 CO.sub.3 /TBAB                      1AR                               NMP     145-146 EtOH                                                                            69                                                          K.sub.2 CO.sub.3                                                                      166-167.sup.(g) EtOH                1AS                                                                              CH(CH.sub.3).sub.2                                                                     2,6-Cl.sub.2 -3-[OCH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                         ]-C.sub.6 H.sub.2     DMF     190-191.sup.(b)                                                                         31                           6-CH.sub.3 O                   K.sub.2 CO.sub.3 (3 eq)                                                               CH.sub.3 CN/Et.sub.2 O              1AT                                                                              CH(CH.sub.3).sub.2                                                                     2,6-Cl.sub.2 -3-(OCH.sub.2 CH.sub.2 -1-pyr)-C.sub.6 H.sub.2                                         DMF     165-167.sup.(b)                                                                         36                           6-CH.sub.3 O                   K.sub.2 CO.sub.3 (3 eq)                                                               CH.sub.3 CN/Et.sub.2 O              1AU                                                                              CH(CH.sub.3).sub.2                                                                     2,6-Cl.sub.2 -3-(OCH.sub.2 CH.sub.2 -1-pid)-C.sub.6 H.sub.2                                         DMF     181-184.sup.(b)                                                                         38                           6-CH.sub.3 O                   K.sub.2 CO.sub.3 (3 eq)                                                               CH.sub.3 CN/Et.sub.2 O              1AV                                                                              CH(CH.sub.3).sub.2                                                                     2,6-Cl.sub.2 -3-(OCH.sub.2 CH.sub.2 NEt.sub.2)-C.sub.6                        H.sub.2               DMF     165-167.sup.(b)                                                                         63                           6-CH.sub.3 O                   K.sub.2 CO.sub.3 (3 eq)                                                               CH.sub.3 CN/Et.sub.2 O              1AW                                                                              CH(CH.sub.3).sub.2                                                                     2,6-Cl.sub.2 -C.sub.6 H.sub.3                                                                       DMF     101-110   87                           6-OH                           Cs salt                                     1AX                                                                              CH(CH.sub.3).sub.2                                                                     2,6-Cl.sub.2 -3-(OCH.sub.2 CH.sub.2 -4-Mor)-C.sub.6 H.sub.2                                         DMF     amorphous 87                           6-OEt                          Cs salt                                     1AY                                                                              C.sub.2 H.sub.5                                                                        2,6-Cl.sub.2 C.sub.6 H.sub.3                                                                        DMF     193-195   71                           5,7-(CH.sub.3 O).sub.2         K.sub.2 CO.sub.3 /TBAB                                                                iPrOH                               1AZ                                                                              CH(CH.sub.3).sub.2                                                                     2,6-Cl.sub.2 -C.sub.6 H.sub.3                                                                       DMF     183-185.sup.(b)                                                                         --                           6-(4-CH.sub.3 -1-pip)          K.sub.2 CO.sub.3                                                                      EtOH/Et.sub.2 O                     1BA                                                                              n-C.sub.3 H.sub.7                                                                      2,6-Cl.sub.2 -C.sub.6 H.sub.3                                                                       DMF     138-140   79                           5,6-(CH.sub.3 O).sub.2         K.sub.2 CO.sub.3                                                                      iPrOH/hex                           1BB                                                                              CH(CH.sub.3).sub.2                                                                     2,6-Cl.sub.2 -C.sub.6 H.sub.3                                                                       DMF     171-173   75                           5,6-(CH.sub.3 O).sub.2         K.sub.2 CO.sub.3                                                                      iPrOH                               1BC                                                                              CH(CH.sub.3).sub.2                                                                     2,6-Cl.sub.2 -C.sub.6 H.sub.3                                                                       DMF     138-139   17                           6-F                            K.sub.2 CO.sub.3                                                                      iPrOH/hex                           1BD                                                                              n-C.sub.3 H.sub.7                                                                      2,6-Cl.sub.2 -3-(OCH.sub.2 CH.sub.2 -4-Mor)-C.sub.6 H.sub.                                          DMF     183-185.sup.(b)                                                                         48                           5,6-(CH.sub.3 O).sub.2         K.sub.2 CO.sub.3                                                                      iPrOH/ether                         1BE                                                                              CH(CH.sub.3).sub.2                                                                     3-P(O)(OEt).sub.2 -C.sub.6 H.sub.4                                                                  DMF     oil from  56                                                                  chromatography                         6-CH.sub.3 O                   K.sub.2 CO.sub.3                                                                      SiO.sub.2 -EtOAc/hex                1BF                                                                              CH(CH.sub.3).sub.2                                                                     2,6-Cl.sub.2 -C.sub.6 H.sub.3                                                                       CH.sub.3 CN                                                                           130-132   23                           6,7-(CH.sub.3 O).sub.2         DIPEA                                       1BG                                                                              CH(CH.sub.3).sub.2                                                                     2,6-Cl.sub.2 -C.sub.6 H.sub.3                                                                       CH.sub.3 CN                                                                           160-162                                6,7-(--OCH.sub.2 O--)          DIPEA   SiO.sub.2 -MDC/Me.sub.2                                                                 61                        1BH                                                                              CH(CH.sub.3).sub.2                                                                     2,6-Cl.sub.2 -3-[SO.sub.2 -(4-CH.sub.3 -1-pip)]-C.sub.6                       H.sub.2               CH.sub.3 CN                                                                           176-182   67                           6,7-(CH.sub.3 O).sub.2         DIPEA   ether                               1BI                                                                              CH(CH.sub.3).sub.2                                                                     2,6-Cl.sub.2 -3-[SO-(4-CH.sub.3 -1-pip)]-C.sub.6 H.sub.2                                            CH.sub.3 CN                                                                           198-200   51                           6,7-(--OCH.sub.2 O--)          DIPEA   ether/hexane                        1BJ                                                                              CH(CH.sub.3).sub.2                                                                     2,6-Cl.sub.2 -3(OCH.sub.2 CH.sub.2 -4-Mor)-C.sub.6 H.sub.2                                          CH.sub.3 CN                                                                           160-170.sup.(b)                                                                         40                           6,7-(--OCH.sub.2 O--)          DIPEA   ether                               1BK                                                                              CH(CH.sub.3).sub. 2                                                                    2,6-(CH.sub.3 O).sub.2 --C.sub.6 H.sub.3                                                            CH.sub.3 CN                                                                           167-168   73                           6-CH.sub.3 O                   DIPEA                                       1BL                                                                              CH(CH.sub.3).sub.2                                                                     2,6-F.sub.2 -C.sub.6 H.sub.3                                                                        CH.sub.3 CN                                                                           128-129   62                           6-CH.sub.3 O                   DIPEA                                       1BM                                                                              CH(CH.sub.3).sub.2                                                                     2,6-(CH.sub.3).sub.2 --C.sub.6 H.sub.3                                                              CH.sub.3 CN                                                                           157-158   81                           6-CH.sub.3 O                   DIPEA                                       1BN                                                                              CH(CH.sub.3).sub.2                                                                     2,6-(CH.sub.3 O).sub.2 -3-NO.sub.2 --C.sub.6 H.sub.2                                                CH.sub.3 CN                                                                           79-81     24                           6-CH.sub.3 O                   DIPEA                                       1BO                                                                              CH(CH.sub.3).sub.2                                                                     2,4,6-(CH.sub.3 O).sub.3 --C.sub.6 H.sub.2                                                          CH.sub.3 CN                                                                           150-151   87                           6-CH.sub.3 O                   DIPEA                                       1BP                                                                              CH(CH.sub.3).sub.2                                                                     2,6-(CH.sub.3 O)2-4-BzlO--C.sub.6 H.sub.2                                                           CH.sub.3 CN                                                                           178-179   71                           6-CH.sub.3 O                   DIPEA                                       1BQ                                                                              CH(CH.sub.3).sub.2                                                                     2,6-F.sub.2 -4-CH.sub.3 O--C.sub.6 H.sub.2                                                          CH.sub.3 CN                                    6-CH.sub.3 O                   DIPEA                                       1BR                                                                              CH(CH.sub.3).sub.2                                                                     2,6-(CH.sub.3 O).sub.2 -3-NHAc--C.sub.6 H.sub.2                                                     CH.sub.3 CN                                                                           183-184   74                           6-CH.sub.3 O                   DIPEA                                       1BS                                                                              CH(CH.sub. 3).sub.2                                                                    2-CH(CH.sub.3).sub.2 --C.sub.6 H.sub.4                                                              CH.sub.3 CN                                                                           144-146   63                           6-CH.sub.3 O                   DIPEA                                       1BT                                                                              CH(CH.sub.3).sub.2                                                                     2,6-Cl.sub.2 --C.sub.6 H.sub.3                                                                      DMF     foam       9                           6-N(CH.sub.3).sub.2 -7-Cl      TBAB/K.sub.2 CO.sub.3                       1BU                                                                              CH(CH.sub.3).sub.2                                                                     2,6-Cl.sub.2 -3-BzlO--C.sub.6 H.sub.2                                                               DMF     139-140   89                           6-CH.sub.3 O                   K.sub.2 CO.sub.3                                                                      MDC/hex                             1BV                                                                              CH(CH.sub.3).sub.2                                                                     2,6-Cl.sub.2 -3-(SO.sub.2 NHCH.sub.2 COOBzl)C.sub.6 H.sub.2                                         DMF     not       53                                                                  crystallized                           6-CH.sub.3 O                   K.sub.2 CO.sub.3                            1BW                                                                              CH(CH.sub.3).sub.2                                                                     2,6-Cl.sub.2 -3-[SO.sub.2 -(4-CH-1-pip)]C.sub.6 H.sub.2                                             DMF     208-211.sup.(b)                                                                         47                           6-OH                           TBAB/K.sub.2 CO.sub.3                       1BX                                                                              C(CH.sub.3).sub.3                                                                      2,6-Cl.sub.2 --C.sub.6 H.sub.3                                                                      DMF     162-163   78                           H                              K.sub.2 CO.sub.3                                                                      MDC/ether/hex                       1BY                                                                              CH(CH.sub.3).sub.2                                                                     2,6-Cl.sub.2 -4-(OCH.sub.2 CH.sub.2 -4-Mor)C.sub.6 H.sub.2                                          DMF     138-140.sup.(b)                                                                         65                           H                              TBAB/K.sub.2 CO.sub.3                       1BZ                                                                              CH(CH.sub.3).sub.2                                                                     2,6-(CH.sub.3).sub.2 -4-BzlO-C.sub.6 H.sub.2                         6-CH.sub.3 O                                                               __________________________________________________________________________     .sup.(a) 2Chloromethylsaccharin reacted with                                  2,6dichloro-3-carbo-t-butoxycarbonyl-methyl-aminosulfonylbenzoic acid and     the product hydrolyzed with trifluoroacetic acid in MDC to give the           corresponding 2saccharinylmethyl carboxymethylamino-sulfonylbenozate in       76% yield.                                                                    .sup.(b) HCl salt.                                                            .sup.(c) 2Chloromethyl-4-isopropylsaccharin reacted with                      2,6dichloro-3-benzyloxy-carbonylmethylaminosulfonylbenzoic acid and the       product catalytically debenzylated under 1 atm. of hydrogen over              palladium/charcoal in EtOAc with 17% acetic acid to give the correspondin     acid in 80% yield.                                                            .sup.(d) 2Chloromethyl-4-isopropylsaccharin reacted with                      2,6dichloro-3-benzyloxybenozoic acid, and two products were obtained, one     in which the benzoic acid moiety had been dechlorinated.                      .sup.(e) HCl.5/2 H.sub.2 O.                                                   .sup.(f) HCl.3/2 H.sub.2 O.                                                   .sup.(g) CH.sub.3 SO.sub.3 H salt.                                       

EXAMPLE 1AW

The cesium salt of 2,6-dichlorobenzoic acid as prepared from 4.48 g(0.0235 mol) of 2,6-dichlorobenzoic acid and 3.82 g (0.0117 mol) ofCsCO₃ in methanol. The salt was isolated by removing the solvent underreduced pressure and drying under high vacuum for 1/2 hr. The dried saltwas suspended by stirring in 10-15 mL of DMF and 3.4 g (0.0117 mol) of2-chloromethyl-6-hydroxy-4-isopropylsaccharin was added. The mixture washeated at 80° for 2-3 hr, cooled, diluted with water and extracted with200 mL of 7:3 ether:ethyl acetate. The organic layer was washed withwater and saturated NaCl and dried. The solvent was removed and theresidue was purified by flash chromatography with ethyl acetate-hexaneon silica gel to give 4.53 (87%) of6-hydroxy-4-isopropyl-2-saccharinylmethyl-2,6-dichlorobenozic (no mp).

EXAMPLE 2A

A solution of 1.4 g (0.0026 mol) of 4-isopropyl-2-saccharinylmethyl2,6-dichloro-3-benzyloxybenzoate in 50 ml of ethyl acetate was treatedwith 0.3 g of 10% palladium-on-charcoal and 0.5 ml of acetic acid andthe mixture stirred under 1 atm. of hydrogen for sixteen hours. Thecatalyst was removed by filtration, and the filtrate was taken todryness in vacuo to give 1.16 g (100%) of4-isopropyl-2-saccharinylmethyl 2,6-dichloro-3-hydroxybenzoate, m.p.78°-80° C.

EXAMPLE 2B

Following a procedure similar to that described in Example 2A above, 1.2g (0.0018 mol) of 4-isopropyl-2-saccharinylmethyl2,6-dichloro-3-(4-benzyl-l-piperazinylsulfonyl)benzoate (Example 1Z) wasreduced with hydrogen in 50 ml of ethyl acetate and 2 ml of acetic acidover 0.3 g of 10% palladium-on-charcoal and the product converted to thehydrochloride salt to give 0.5 g (68%) of4-isopropyl-2-saccharinylmethyl2,6-dichloro-3-(1-piperazinylsulfonyl)benzoate hydrochloride, m.p. above171° C.

EXAMPLE 2C

A mixture of4-isopropyl-6-methoxy-2-saccharinylmethyl-2,6-dichloro-3-benzyloxybenzoateof Example 1BU (2.5 g, 4.4 mmol), 10% Pd on Carbon (0.7g) and glacialacetic acid (1 mL in ethyl acetate (100 mL) was stirred under 50 psihydrogen in a Parr hydrogenator for 1.5 hr. The resulting mixture wasfiltered through a pad of super cel eluting with ethyl acetate (100 mL).The combined filtrate was washed with saturated NaHCO₃, water, brine anddried. Removal of the solvent in vacuo and crystallization from 1:1ether/hexanes gave 2.1 g (100%) of4-isolpropyl-6-methoxy-2-saccharinylmethyl2,6-dichloro-3-hydroxybenzoate, mp 152°-154°.

EXAMPLE 2D

By a process analogous to that of Example 2A, 0.41 g of4-isopropyl-6-methoxy-2-saccharinylmethyl2,6-dichloro-3-benzyloxycarbonylmethylaminosulfonylbenzoate of Example1BV was catalytically debenzylated under 1 atm. of hydrogen overpalladium/charcoal in ethyl acetate with 20% acetic acid to give 0.16 g(45%) 4-isopropyl-6-methoxy-2-saccharinylmethyl2,6-dichloro-3-carboxymethylaminosulfonylbenzoate, mp 204°-206°.

EXAMPLE 3A

A solution of 1.05 g (0.0024 mol) of 4-isopropyl-2-saccharinylmethyl2,6-dichloro-3-hydroxybenzoate (Example 2A), 0.50 g (0.0026 mol) oft-butyl alpha-bromoacetate and 0.48 g (0.0035 mol) of potassiumcarbonate in 25 ml of acetone was heated under reflux for seven hours,then cooled to ambient temperature, filtered and the filtrate taken todryness to give 0.32 g (24%) of 4-isopropyl-2-saccharinylmethyl2,6-dichloro-3-t-butoxycarbonylmethoxybenzoate, which was dissolved in10 ml of MDC containing 2 ml of trifluoroacetic acid. The solution wasstirred at ambient temperature under nitrogen for two hours, taken todryness and the residue triturated with hexane/ether. The resultingsolid was collected by filtration to give 0.18 g (64%) of4-isopropyl-2-saccharinylmethyl 2,6-dichloro-3-carboxymethoxybenzoate,m.p. 210°-212° C.

EXAMPLE 3B

A solution of 0.78 g (1.6 mmol) of4-isopropyl-6-methoxy-2-saccharinylmethyl-2,6-dichloro-3-hydroxybenzoate,0.38 g (2.0 mmol) of t-butyl α-bromoacetate and 0.3 g (2.1 mmol) ofpotassium carbonate in 50 mL acetone was heated under reflux for 16 h,then cooled to room temperature, filtered and the filtrate taken todryness. Purification of the residue by flash chromatography on silicagel (4:2 hexanes:ethyl acetate) gave 0.65 g (67%) of4-isopropyl-6-methoxy-2-saccharinylmethyl2,6-dichloro-3-t-butoxycarbonylmethoxybenzoate. The t-butyl ester (0.55g, 0.9 mmol) was dissolved in 15 mL MDC containing 5 mL oftrifluoroacetic acid. The solution was stirred at room temperature undernitrogen for 2 hr, taken to dryness and the residue triturated withhexane/ether. The resulting solid was collected by filtration to give0.4 (82%) of 4-isopropyl-6-methoxy-2-saccharinylmethyl2,6-dichloro-3-carboxymethoxybenzoate, mp 206°-208°.

EXAMPLE 4

By reaction of an appropriate 4-R⁴ -R⁵ -2-halomethylsaccharin of formulaIV with an appropriate arylcarboxylic acid using the procedure describedabove in Example 1A, or by reaction of the appropriate saccharin offormula II with the appropriate chloromethyl benzoate using theprocedure described in Example 11 below, the compounds of formula Ilisted in TABLE 2 below can be prepared.

                                      TABLE 2                                     __________________________________________________________________________    Example                                                                              R.sup.4 R.sup.5       Ar                                               __________________________________________________________________________    4A     Br      H             2,6-Cl.sub.2 4-NH.sub.2 C.sub.6 H.sub.2          4B     Cl      H             2,6-Cl.sub.2 -3-(CONH.sub.2)C.sub.6 H.sub.2      4C     CH.sub.3 O                                                                            H             2,6-Cl.sub.2 C.sub.6 H.sub.3                     4D     CH(C.sub.2 H.sub.5).sub.2                                                             H             2,6-Cl.sub.2 H.sub.6 H.sub.3                     4E     CH.sub.3 O                                                                            6-CH.sub.3 O  2,6-Cl.sub.2 H.sub.6 H.sub.3                     4F     H       7-Cl          2,6-Cl.sub.2 H.sub.6 H.sub.3                     4G     CH.sub.3                                                                              5-CH.sub.3 O  3-(CH.sub.3 NHCH.sub.2 CH.sub.2)C.sub.6                                       H.sub.4                                          4H     COOCH.sub.3                                                                           H             2,6-Cl.sub.2 H.sub.6 H.sub.3                     4I     C.sub.2 H.sub.5 O                                                                     H             2,6-Cl.sub.2 H.sub.6 H.sub.3                     4J     (CH.sub.3).sub.2 CHO                                                                  H             2,6-Cl.sub.2 H.sub.6 H.sub.3                     4L     H       6-NO.sub.2    2,6-Cl.sub.2 H.sub.6 H.sub.3                     4M     H       5-(CH.sub.3).sub.3 CCH.sub.2 C(CH.sub.3).sub.2                                              2,6-Cl.sub.2 H.sub.6 H.sub.3                     4N     H       4,7-(CH.sub.3 O).sub.2                                                                      2,6-Cl.sub.2 H.sub.6 H.sub.3                     4-O    C.sub.2 H.sub.5 O                                                                     7-CH.sub.3 (OCH.sub.2 CH).sub.2 O                                                           2,6-Cl.sub.2 H.sub.6 H.sub.3                     4P     CH.sub. 3 O                                                                           7-CH.sub.3 (OCH.sub.2 CH).sub.2 O                                                           2,6-Cl.sub.2 H.sub.6 H.sub.3                     4Q     n-C.sub.3 H.sub.7                                                                     H             2,6-Cl.sub.2 H.sub.6 H.sub.3                     4R     CH.sub.3                                                                              7-CH.sub.3    3-[(CH.sub.3).sub.2 NCH.sub.2 CH.sub.2                                        OOC]C.sub.6 H.sub.4                              4T     CF.sub.3                                                                              H             3-[(CH.sub.3).sub.2 NCH.sub.2 CH.sub.2                                        NH]C.sub.6 H.sub.4                               4U     CCl.sub.3                                                                             H             2,6-Cl.sub.2 H.sub.6 H.sub.3                     4V     H       6-cyclohexyl  2,6-Cl.sub.2 H.sub.6 H.sub.3                     4W     H       6-CH.sub.3 SO.sub.2 NH                                                                      2,6-Cl.sub.2 H.sub.6 H.sub.3                     4X     H       6-CF.sub.3 SO.sub.2 NH                                                                      2,6-Cl.sub.2 H.sub.6 H.sub.3                     4Y     H       6-CCl.sub.3 SO.sub.2 NH                                                                     2,6-Cl.sub.2 H.sub.6 H.sub.3                     4Z     H       6-CN          2,6-Cl.sub.2 H.sub.6 H.sub.3                     4AA    H       6-NH.sub.2 SO.sub.2                                                                         2,6-Cl.sub.2 H.sub.6 H.sub.3                     4AB    H       6-CH.sub.3 SO.sub.2 NHSO.sub.2                                                              2,6-Cl.sub.2 H.sub.6 H.sub.3                     4AC    H       6-CH.sub.3 SO.sub.2                                                                         2,6-Cl.sub.2 H.sub.6 H.sub.3                     4AD    H       6-CF.sub.3 SO.sub.2                                                                         2,6-Cl.sub.2 H.sub.6 H.sub.3                     4AE    H       6-HOOC        2,6-Cl.sub.2 H.sub.6 H.sub.3                     4AF    H       6-HOCH.sub.2  2,6-Cl.sub.2 C.sub.6 H.sub.3                     4AG    H       6-OHC         2,6-Cl.sub.2 H.sub. 6 H.sub.3                    4AH    H       6-NH.sub.2 CH.sub.2                                                                         2,6-Cl.sub.2 H.sub.6 H.sub.3                     4AI    H       6-CF.sub.3    3-(1-azet)C.sub.6 H.sub.4                        4AJ    H       6-CCl.sub.3   2,6-Cl.sub.2 H.sub.6 H.sub.3                     4AK    CH═CH.sub.2                                                                       H             2,6-Cl.sub.2 H.sub.6 H.sub.3                     4AL    C.tbd.CH                                                                              H             2,6-Cl.sub.2 H.sub.6 H.sub.3                     4AM    NH.sub.2                                                                              H             2,6-Cl.sub.2 H.sub.6 H.sub.3                     4AN    CH.sub.3 NH                                                                           H             1-(1-imidazol)C.sub.6 H.sub.4                    4AO    (CH.sub.3).sub.2 N                                                                    H             2,6-Cl.sub.2 H.sub.6 H.sub.3                     4AP    CH(CH.sub.3).sub.2                                                                    6-CH.sub.3 S  2,6-Cl.sub.2 H.sub.6 H.sub.3                     4AQ    CH(CH.sub.3).sub.2                                                                    6-CH.sub.3 SO 2,6-Cl.sub.2 H.sub.6 H.sub.3                     4AR    CH(CH.sub.3).sub.2                                                                    6-CH.sub.3 SO.sub.2                                                                         2,6-Cl.sub.2 H.sub.6 H.sub.3                     4AS    CH(CH.sub.3).sub.2                                                                    6-F           3-(1-pyr.)C.sub.6 H.sub.4                        4AT    CH(CH.sub.3).sub.2                                                                    6-C.sub.6 H.sub.5 S                                                                         2,6-Cl.sub.2 H.sub.6 H.sub.3                     4AU    CH(CH.sub.3).sub.2                                                                    6-(4-CH.sub.3 C.sub.6 H.sub.4 S)                                                            2,6-Cl.sub.2 H.sub.6 H.sub.3                     4AV    CH(CH.sub.3).sub.2                                                                    6-(4-CH.sub.3 OC.sub.6 H.sub.4 S)                                                           2,6-Cl.sub.2 H.sub.6 H.sub.3                     4AW    CH(CH.sub.3).sub.2                                                                    6-(4-ClC.sub.6 H.sub.4 S)                                                                   2,6-Cl.sub.2 H.sub.6 H.sub.3                     4AX    CH(CH.sub.3).sub.2                                                                    6-(4-ClC.sub.6 H.sub.4 S)                                                                   2,6-Cl.sub.2 H.sub.6 H.sub.3                     4AY    CH(CH.sub.3).sub.2                                                                    6-(1-naphthyl-S)                                                                            2,6-Cl.sub.2 H.sub.6 H.sub.3                     4AZ    CH(CH.sub.3).sub.2                                                                    6-C.sub.6 H.sub.5 SO                                                                        2,6-Cl.sub.2 H.sub.6 H.sub.3                     4BA    CH(CH.sub.3).sub.2                                                                    6-C.sub.6 H.sub.5 SO.sub.2                                                                  2,6-Cl.sub.2 H.sub.6 H.sub.3                     4BB    CH(CH.sub.3).sub.2                                                                    6-(4-CH.sub.3 C.sub.6 H.sub.4 SO)                                                           2,6-Cl.sub.2 H.sub.6 H.sub.3                     4BC    CH(CH.sub.3).sub.2                                                                    6-(4-CH.sub.3 C.sub.6 H.sub.4 SO.sub.2)                                                     2,6-Cl.sub.2 H.sub.6 H.sub.3                     4BD    CH(CH.sub.3).sub.2                                                                    6-(4-CH.sub.3 OC.sub.6 H.sub.4 SO)                                                          2,6-Cl.sub.2 H.sub.6 H.sub.3                     4BE    CH(CH.sub.3).sub.2                                                                    6-(4-CH.sub.3 OC.sub.6 H.sub.4 SO.sub.2)                                                    2,6-Cl.sub.2 H.sub.6 H.sub.3                     4BF    CH(CH.sub.3).sub.2                                                                    6-(4-ClC.sub.6 H.sub.4 SO)                                                                  2,6-Cl.sub.2 H.sub.6 H.sub.3                     4BG    CH(CH.sub.3).sub.2                                                                    6-(4-ClC.sub.6 H.sub.4 SO.sub.2)                                                            2,6-Cl.sub.2 H.sub.6 H.sub.3                     4BH    CH(CH.sub.3).sub.2                                                                    6-(4-CH.sub.3 -1-naphthyl-SO)                                                               2,6-Cl.sub.2 H.sub.6 H.sub.3                     4BI    CH(CH.sub.3).sub.2                                                                    6-(4-CH.sub.3 -1-naphthyl-SO.sub. 2)                                                        2,6-Cl.sub.2 H.sub.6 H.sub.3                     4BJ    CH(CH.sub.3).sub.2                                                                    6-(1-naphthyl-SO)                                                                           2,6-Cl.sub.2 H.sub.6 H.sub.3                     4BK    CH(CH.sub.3).sub.2                                                                    6-(1-naphthyl-SO.sub.2)                                                                     2,6-Cl.sub.2 H.sub.6 H.sub.3                     4BL    CH(CH.sub.3).sub.2                                                                    6-CH.sub.3 COO                                                                              2,6-Cl.sub.2 H.sub.6 H.sub.3                     4BM    CH(CH.sub.3).sub.2                                                                    6-C.sub.6 H.sub.5 COO                                                                       2,6-Cl.sub.2 H.sub.6 H.sub.3                     4BN    CH(CH.sub.3).sub.2                                                                    6-(1-naphthyl-COO)                                                                          2,6-Cl.sub.2 H.sub.6 H.sub.3                     4BO    CH(CH.sub.3).sub.2                                                                    6-(1-azetidinyl)                                                                            2,6-Cl.sub.2 H.sub.6 H.sub.3                     4BP    CH(CH.sub.3).sub.2                                                                    6-(1-pyrrolidinyl)                                                                          2,6-Cl.sub.2 H.sub.6 H.sub.3                     4BQ    CH(CH.sub.3).sub.2                                                                    6-(1-piperidinyl)                                                                           2,6-Cl.sub.2 H.sub.6 H.sub.3                     4BR    CH(CH.sub.3).sub.2                                                                    6-(4-morpholinyl)                                                                           2,6-Cl.sub.2 H.sub.6 H.sub.3                     4BS    CH(CH.sub.3).sub.2                                                                    6-(4-benzyl-1-piperazinyl)                                                                  2,6-Cl.sub.2 H.sub.6 H.sub.3                     4BT    CH(CH.sub.3).sub.2                                                                    6-(4-methyl-1-piperazinyl)                                                                  2,6-Cl.sub.2 H.sub.6 H.sub.3                     4BU    CH(CH.sub.3).sub.2                                                                    6-(1-1H-imidazolyl)                                                                         2,6-Cl.sub.2 H.sub.6 H.sub.3                     4BV    CH(CH.sub.3).sub.2                                                                    6-(NHCH.sub.2 COOC.sub.4 H.sub.9 -t)                                                        2,6-Cl.sub.2 H.sub.6 H.sub.3                     4BW    CH(CH.sub.3).sub.2                                                                    6-NH.sub.2    2,6-Cl.sub.2 H.sub.6 H.sub.3                     4BX    CH(CH.sub.3).sub.2                                                                    6-(1-piperazinyl)                                                                           2,6-Cl.sub.2 H.sub. 6 H.sub.3                    4BY    CH(CH.sub.3).sub.2                                                                    6-(NHCH.sub.2 COOH)                                                                         2,6-Cl.sub.2 H.sub.6 H.sub.3                     4BZ    CH(CH.sub.3).sub.2                                                                    6-(CH.sub.3 CONH)                                                                           2,6-Cl.sub.2 H.sub.6 H.sub.3                     4CA    CONH.sub.2                                                                            H             2,6-Cl.sub.2 C.sub.6 H.sub.3                     __________________________________________________________________________

EXAMPLE 4CB

According to the procedure of Example 4,2-chloromethyl-4-spirocyclopropyl-4,5,6,7-tetrahydrosaccharin ofpreparation 19BI is coupled with 2,6-dimethylbenzoic acid to provide4-spirocyclopropyl-4,5,6,7-tetrahydro-2-saccharinylmethyl2,6-dimethylbenzoate.

EXAMPLE 4CC

According to the procedure of Example 4,2-chloromethyl-4-isopropyl-6-methoxy-4,5,6,7-tetrahydrosaccharin ofpreparation 19BJ is coupled with 2,6-dimethylbenzoic acid to provide4-isopropyl-6-methoxy-4,5,6,7-tetrahydro-2-saccharinylmethyl2,6-dimethylbenzoate.

EXAMPLE 5A

To a solution of 500 mg (1.1 mmol) of6-hydroxy-4-isopropyl-2-saccharinylmethyl 2,6-dichlorobenzoate in 10-15ml of THF were added 298 mg (1.14 mmol) of triphenylphosphine, 52 mg(1.13 mmol) of ethanol and 198 mg (1.14 mmol) of diethylazodicarboxylate at RT. The mixture was stirred for 11/2 hr and thenchromatographed on silica gel with 10% ethyl acetate in hexane to yield370 mg (70%) of 6-ethoxy-4-isopropyl-2-saccharinylmethyl2,6-dichlorobenzoate as a white powder, mp 140°-141° C.

Following the procedure of Example 5A, the compounds of Table 3 wereprepared from the 6-hydroxy compound of Example 1AW.

                  TABLE 3                                                         ______________________________________                                                                             yield                                    Example R5                 mp        (%)                                      ______________________________________                                        5B      6-iPrO             114-115   73                                       5C                                                                                     ##STR12##         123-125   70                                       5D      6-(OCH.sub.2 CH.sub.2).sub.2 OCH.sub.3                                                           119-120   74                                       5E      6-OCH.sub.2 COOCH.sub.3                                                                          foam      64                                       5F      6-OCH.sub.2 CH(OCH.sub.3)CH.sub.2 OCH.sub.3                                                      gum       53                                       5G      6-O-cyclobutyl     150-151   44                                       ______________________________________                                    

The protected glycerol used in the synthesis of Example 5F was obtainedas follows:

A solution of 10.0 g (0.055 mol) of DL-α-O-benzylglycerol in a littleTHF was added to a suspension of 15.38 g (0.137 mol) of potassiumtert-butoxide in 300 mL of THF. The mixture was stirred for 1 hr at RTand 18.72 (0.132 mol) of iodomethane was added. A white solidimmediately separated. The reaction was stirred for 10 hr at RT, cooled,carefully diluted with sodium chloride solution and extracted withether. The organic layer was washed with water, 5% HCl, water andsaturated NaCl and dried. The solvent was removed and the residue waspurified by flash chromatography to give1-benzyloxy-2,3-dimethoxypropane, 9.16 g (79%), as an oil.

A solution of 8.8 g (0.042 mol) of this material in 200 ml of MEOH washydrogenated using 1.1 g of 10% Pd/C at 50 psi. The catalyst was removedby filtration and the solvent under reduced pressure-to give 4.4 g (87%)of 2,3-dimethoxy-1-propanol.

EXAMPLE 5I

6-Ethoxy-4-isopropyl-2-phenylthiomethylsaccharin was prepared from the6-hydroxy analog (Preparation 19) by the procedure of Example 5A in 85%yield as a solid, mp 111.5°-112.5° C., which was converted to2-chloromethyl-6-ethoxy-4-isopropylsaccharin in 91% yield, mp 127°-128°C., following the procedure of Preparation 18A.

EXAMPLE 5J

To a solution of 4-isopropyl-6-hydroxysaccharinylmethyl2,6-dichlorobenzoate of Example 1C (0.44 g, 1.0 mmol) in MDC (20 mL) wasadded at 0° C. triethylamine (0.3 g, 3.0 mmol) andtrifluoromethanesulfonic anhydride (0.37 g, 1.3 mmol). After beingstirred at 0° C. for 10 min, the reaction mixture was diluted with MDC(50 mL) and washed with saturated NaHCO₃, brine and dried. Removal ofthe solvent in vacuo and purification of the residue by chromatographyon silica gel (5% ethyl acetate in MDC) gave 0.53 g (88%) of4-isopropyl-6-trifluoromethanesulfonyloxysaccharinylmethyl2,6-dichlorobenzoate as a colorless foam.

The trifluoromethanesulfonate (0.28 g, 0.49 mmol) was mixed with1-methyl-2-trimethylstannyl-pyrrole (0.19 g, 0.78 mmol), tetrakis(triphenylphosphine) palladium (O) (0.012 g, 0.01 mmol), lithiumchloride (0.062 g, 1.5 mmol) and 2,6-di-tert-butyl-4-methyl-phenol (0.01g, 0.05 mmol) in p-dioxane (10 mL) and refluxed under nitrogen for 30min. The resulting dark reaction mixture was cooled to room temperature,diluted with ether (50 mL) and filtered through a pad of super cel. Thefiltrate was washed with water, brine and dried. Removal of the solventin vacuo and purification of the residue by flash chromatography onsilica gel (7:2:1, hexanes:MDC:ether) gave 0.22 g (92%) of4-isopropyl-6-[2-[1-methyl]pyrolyl]saccharinylmethyl2,6-dichlorobenzoate as a pale yellow solid, mp 125°-127° C.

EXAMPLE 5K

4-Isopropyl-6-trifluoromethanesulfonyloxysaccharinylmethyl2,6-dichlorobenzoate, prepared as in Example 5J, (0.7 g, 1.2 mmol) inTHF (10 mL) was cooled to -5° C. and was treated with 40% aqueousdimethylamine (0.6 mL, 5.3 mmol) and stirred at room temperatureovernight. The resulting mixture was diluted with saturated NaHCO₃solution (20 mL) and MDC (250 mL). The layers were separated and theorganic phase washed with water, brine and dried. Removal of the solventin vacuo and purification of the residue by chromatography on silica gel(6:3:1, hexanes:MDC:ether) gave 0.2 g (35%) of4-isopropyl-6-dimethylaminosaccharinylmethyl 2,6-dichlorobenzoate. mp177°-179°.

EXAMPLE 5L

A solution of 42 mg of 4-isopropyl-6-hydroxysaccharinylmethyl2,6-dichlorobenzoate of Example 1C, di-(sec-butoxymethyl)methylamine andtoluene was heated at 80° for 1 hour, cooled and volatiles removed.Slurrying in hexane yielded 30 mg of2-(2,6-dichlorobenzoyloxymethyl)-4-isopropyl-8-methyl-2,3,7-tetrahydro-9H-[1,3]oxazino[6,5-g]benzisothiazol-3-one-1,1-dioxide.

EXAMPLE 6

A solution of 600 mg (1.1 mmol) of the isopropylidene of Example 5C,Table 3, and 176 mg (0.9 mmol) of p-toluenesulfonic acid monohydrate inmethanol-chloroform was stirred overnight. The mixture waschromatographed on silica gel to give 290 mg (53%) of6-(2,3-dihydroxypropoxy)-4-isonpropylsaccharinylmethyl2,6-dichlorobenzoate as a foam.

EXAMPLE 7A

To a solution of 1.0 g (2.3 mmol) of6-hydroxy-4-isopropyl-2-saccharinylmethyl 2,6-dichlorobenzoate in 40 mlof acetone at RT were added 0.62 g (4.5 mmol) of anhydrous K₂ CO₃ and0.66 g (9/3.4 mmol) of t-butyl bromoacetate. The mixture was stirred for4-5 hr and filtered. The filtrate was concentrated under reducedpressure and the residue was purified by flash chromatography to give1.13 g (90%) of6-(2-t-butoxy-2-oxoethoxy)-4-isopropyl-2-saccharinylmethyl2,6-dichlobenzoate as a glass.

EXAMPLE 7B

In a similar manner6-(2-benzyloxy-2-oxoethoxy)-4-isopropyl-2-saccharinylmethyl2,6-dichlorobenzoate was obtained as a glass in 61% yield from the6-hydroxy compound and benzyl bromoacetate.

EXAMPLE 8

To freshly distilled cyclopentadiene (25 mL) at 0° C. was added4-bromo-2-(tert-butyl)isothiaziol-3(2H)-one 1,1-dioxide (Helv. Chim.Acta., 72, 1416, 1989) (7.9 g, 0.03 mol). After stirring at 0` C. undernitrogen for 16 hr, the reaction mixture was concentrated in vacuo. Theresidue was purified by filtering through silica gel, eluting withhexanes (500 mL) followed by 20% ethyl acetate in hexanes (500 mL). Thelatter eluents were concentrated in vacuo to give 9.8 g (100% of thenorbornene adduct,3a-bromo-2-t-butyl-3a,4,7,7a-tetrahydro-4,7-methano-1,2-benzisothiazol-3(2H)-one1,1-dioxide, as a white solid.

The adduct (0.4 g, 1.2 mmol) in 25 mL of ethyl acetate containing 5% Pdon CaCO₃ (0.2 g) was stirred under one atmosphere of hydrogen for 4 hr,and the reaction mixture was filtered through a pad of silica gel,eluting with ethyl acetate (100 mL). The eluents were concentrated invacuo and the residue crystallized from hexanes to give 0.4% (100%) ofthe bromo norbornane as a white crystalline solid.

To a solution of the bromo norbornane (3.7 g, 0.011 mol) in toluene (25mL) at 0° C. was added diazabicyclononene (1.37 g, 0.011 mol) in toluene(10 mL), After stirring at 0° C. for 20 min, silica gel (25 g) was addedto the reaction mixture. The resulting slurry was loaded on top of a 15cm pad of silica gel and eluted with 20% ethyl acetate in hexanes (800mL). The eluents were concentrated in vacuo to give 2.8 (100%) of thedehydrobrominated compound as a white solid.

The 2-t-butyl-4,5,6,7-tetrahydro-4,7-methano-1,2-benzisothiazol-3(2H)one1,1-dioxide (2.8 g, 0.011 mol) in trifluoroacetic acid (30 mL) washeated at reflux for 48 hr and let stand at room temperature for 4 days.The resulting mixture was concentrated in vacuo, treated with methanol(20 mL) and evaporated to dryness. The residue was taken up in ether(100 mL) and washed with saturated NaHCO₃ (1×50 mL). The layers wereseparated, the aqueous phase acidified to pH 1 with 2N HCl and extractedwith MDC (2×100 mL). The combined organic extracts were dried andconcentrated in vacuo to give 0.9 g (42%) of the bicyclo (2.2.1)saccharin derivative as a white solid.

A mixture of the bicyclo (2,2,1) saccharin derivative (0.9 g, 5 mmol),chloromethyl phenylsulfide (0.07 g, 7 mmol) and tetrabutylammoniumbromide (0.36 g, 0.16 mmol) in toluene (50 mL) was refluxed undernitrogen for 16 hr, cooled to room temperature and evaporated to drynessunder vacuum. The residue was purified by flash chromatography on silicagel (100 g) using 100% MDC as the eluent to give 1.05 (72%) of thesulfide as a viscous oil.

The sulfide (1.05 g, 3 mmol) in dichloromethane (100 mL) was treatedwith sulfuryl chloride (0.66 g, 5 mmol) and stirred for 2 hr. Theresulting yellow solution was diluted with MDC (100 mL), washed withsaturated NaHCO₃ solution, dried and concentrated in vacuo. The residuewas purified by flash chromatography on silica gel (33% MDC in hexanes)to give 0.66 g (81%) of2-chloromethyl-4,5,6,7-tetrahydro-4,7-methano-1,2-benzisothiazol-3(2H)-one1,1-dioxide.

The 2-chloromethyl compound (0.66 g, 2.7 mmol) was treated with2,6-dichlorobenzoic acid (0.56 g, 2.9 mmol), anhydrous potassiumcarbonate (0.55 g, 4.0 mmol) and tetrabutylammonium bromide (0.2 g, 0.6mmol) in DMF (2.5 mL) at 70° C. for 1 hr. The resulting mixture wasconcentrated in vacuo, diluted with ethyl acetate (100 mL) and filtered.The filtrate was washed with water, saturated NaHCO₃, water and brine.The organic phase was concentrated in vacuo, and the residue waspurified by flash chromatography on silica gel (3:6:1,MDC:hexanes:ether) to give 0.5g (47%) of2-(2,6-dichlorobenzoyloxymethyl)4,5,6,7-tetrahydro-4,7-methano-1,2-benzisothiazol-3(2H)-one1,1-dioxide as a colorless foam.

EXAMPLES 8B AND 8C

By a process analagous to that of Example 8A, it is contemplated thatcyclohexadiene and 1,1-dimethylcyclopentadiene may be convertedrespectively to2-(2,6-dichlorobenzcyloxymethyl4,5,6,7-tetrahydro-4,7-ethano-1,2-benzisothiazol-3(2H)-one1,1-dioxide and2-(2,6-dichlorobenzoyloxymethyl)-8,8-dimethyl-4,5,6,7-tetrahydro-4,7-methano-1,2-benzoisothiazol-3(2H)-one1,1-dioxide

EXAMPLE 9A-9D

General procedure for the preparation of methyl-2-alkycyclohexan-6-onecaboxylate: To a suspension of anhydrous CuI (10 mmol) in anhydrous THF(100 mL) was added Me₂ S (100 mmol) and the resulting solution wascooled to -78° C. The Grignard reagent (20 mmol) was added over a periodof 15 min. After being stirred at -78° C. for an hour, a solution ofcyclohexenone (10 mmol) in THF was added and stirring continued foranother 15 min. To the resulting mixture was added HMPA (5 mL) and,after 15 min, methyl cyanoformate (30 mmol) in THF (20 mL) and thereaction warmed to room temperature and stirred overnight. The reactionmixture was quenched with 2N HCl (50 mL). The layers were separated andthe aqueous phase extracted with Et₂ O (1×100 mL). The combined organicextracts were washed with saturated NH₄ Cl solution (3×50 mL), water(2×50 mL), brine (1× 50 mL) and dried (Na₂ SO₄). Removal of the solventin vacuo and purification by either Kugelrohr distillation or flashchromatography afforded the desired methyl 2-alkylcyclohexan-6-onecaboxylate (Table E).

                  TABLE E                                                         ______________________________________                                        Intermediate                                                                              Alkyl   Yield     b.p.                                            ______________________________________                                        B           Me      82        --                                              C           Et      70        100-110° C. (0.2 mm)                     D           iPr     74        106-109° C. (0.5 mm)                     ______________________________________                                    

General procedure for the preparation of methyl2-benzylthio-6-alkylcyclohex-2-ene carboxylate and2-benzylthio-6-alkylcyclohex-1-ene carboxylate: A mixture ofmethyl-2-alkylcyclohexan-6-one carboxylate (1 eq), benzylmercaptan (1.1eq) and the acidic clay montmorillonite, KSF (1.5 times the weight ofmethyl-2-alkylcyclohexan-6-one carboxylate) in anhydrous toluene (50-100mL) was refluxed under nitrogen with azeotropic removal of water for12-14 hr and cooled to room temperature. The solids were filtered offand washed with ether. The combined filtrate was washed with 10% Na₂CO₃, water, brine and dried. Removal of the solvent in vacuo andpurification of the residue by flash chromatography on silica gel (10%ether in hexanes) gave a mixture of methyl2-benzylthio-6-alkylcyclohex-2-ene carboxylate and2-benzylthio-6-alkylcyclohex-1-ene carboxylate (Table F) which was usedin the next step as a mixture.

                  TABLE F                                                         ______________________________________                                        Intermediate                                                                              Alkyl   2Combined Yield of Mixture                                ______________________________________                                        A           H       40                                                        B           Me      44                                                        C           Et      50                                                        D           iPr     52                                                        ______________________________________                                    

General procedure for the preparation of 4-alkyl-tetrahydrosaccharins: Asolution of methyl 2-benzylthio-6-alkylcyclohex-2-ene-carboxylate and2-benzylthio-6-alkylcyclohex-1-ene carboxylate (1-10 mmol of themixture) in 10 mL of MDC was diluted with 20-50 mL of glacial aceticacid and 1-5 mL of water, the mixture cooled to -10° C., and chlorinegas was bubbled through the mixture until the exothermic reactionsubsided. The mixture was then stirred for 10 minutes and taken todryness to give a mixture of methyl2-chlorosulfonyl-6-alkylcyclohex-2-ene carboxylate and2-chlorosulfonyl-6-alkylcyclohex-l-ene carboxylate, which was dissolvedin 10 mL of THF and added to 25 mL of a solution of concentratedammonium hydroxide while cooling in an ice/acetone bath. After stirringfor 2 hr, the reaction mixture was concentrated in vacuo, the residuetaken up in water, acidified to pH 1 with 2N HCl, and extracted withMDC. The organic phase was dried and concentrated in vacuo to give amixture of methyl 2-aminosulfonyl-6-alkylcyclohex-2-ene carboxylate and2-aminosulfonyl-6-alkylcyclohex-l-ene carboxylate. The mixture wasdissolved in methanol and added to a freshly prepared solution of sodiummethoxide (10-50 mmol) and stirred at ambient temperature for 12 hr. Thereaction mixture was concentrated in vacuo, diluted with water andextracted with ether. The organic phase was discarded, and the aqueousphase was acidified to pH 1 with concentrated HCl and extracted withMDC. The organic extracts, on washing with brine, drying and evaporationto dryness, afforded 4-alkyl-4,5,6,7-tetrahydrobenzisothiazol-3-one1,1-dioxide or 4-alkyl-tetrahydro saccharins (Table G).

                  TABLE G                                                         ______________________________________                                        Intermediates    Alkyl   Yield                                                ______________________________________                                        A                H       50                                                   B                Me      85                                                   C                Et      80                                                   D                iPr     74                                                   ______________________________________                                    

A mixture of 4-alkyl-4,5,6,7-tetrahydrobenzisothiazol-3-one 1,1-dioxide(4-alkyltetrahydro saccharin) (1.0 eq), chloromethyl phenyl sulfide (1.5eq) and tetrabutylammonium bromide (0.2 eq) in toluene (25 mL/g ofsaccharin) was refluxed under nitrogen for 16-24 hr and then cooled toroom temperature. The resulting mixture was evaporated to dryness andthe residue chromatographed on silica gel eluting with hexanes/MDC (1:1to 1:3) to give the corresponding2-phenylthiomethyl-4-alkyl-4,5,6,7-tetrahydrobenzisothiazole -3-one1,1-dioxide or 2-phenylthiomethyl-4-alkyl-tetrahydro saccharin (TableH).

                  TABLE H                                                         ______________________________________                                        Example         Alkyl   Yield                                                 ______________________________________                                        A               H       40                                                    B               Me      55                                                    C               Et      40                                                    D               iPr     53                                                    ______________________________________                                    

A solution of 2-phenylthiomethyl-4-alkyl-tetrahydro saccharin (1.0 eq)was treated with sulfuryl chloride (1.5 eq) and stirred for 2 hr. Theresulting yellow solution was taken to dryness to give2-chloromethyl-4-alkyl-tetrahydro saccharin, which was treated with2,6-dichlorobenzoic acid (1.1 eq), anhydrous potassium carbonate (1.5eq) and tetrabutylammonium bromide (0.2 eq) in DMF (25 mL) at 70° C. for1 hr. The resulting mixture was concentrated in vacuo, diluted withethyl acetate (100 mL) and filtered. The filtrate was washed with water,saturated NaHCO₃, water and brine. The organic phase was concentrated invacuo, and the residue purified by flash chromatography on silica gel(2:1 MDC/hexanes) to give 4-alkyl-4,5,6,7-tetrahydro-2-saccharinylmethyl2,6-dichlorobenzoate (Table J).

                  TABLE J                                                         ______________________________________                                        Example     Alkyl      Yield   mp (°C.)                                ______________________________________                                        9A          H          63      93-95                                          9B          Me         54      127-129                                        9C          Et         50      86-89                                          9D          iPr        48      108-110                                        ______________________________________                                    

EXAMPLE 9E

Following a procedure similar to that described for Example 1AA,2-chloromethyl-4-isopropyl-4,5,6,7-tetrahydrobenzisothiazol-3-one1,1-dioxide was treated with2,6-dichloro-3-[[2-(N,N-dimethylamino)ethyl]-N-methylaminosulfonyl]benzoicacid (Preparation 20F) to give4-isopropyl-4,5,6,7-tetrahydro-2-saccharinylmethyl2,6-dichloro-3-[[2-(N,N-dimethylamino)ethyl]-N-methylaminosulfonyl]benzoatehydrochloride, mp 121 (dec).

EXAMPLE 10

Methyl 2,2-dimethylcyclohexan-6-one carboxylate: To a suspension ofanhydrous CuI (70.0 g, 0.37 mol) in anhydrous ether (500 mL) at 0° C.was added halide-free methyl lithium (520 mL of 1.4 M solution in ether,0.73 mol). After being stirred at 0` C. for 15 minutes, a solution of3-methyl-2-cyclohexenone (20.0 g, 0.18 mol) in ether (50 mL) was addedand stirring continued for another 1 hr. To the resulting mixture wasaded THF (50 mL) and HMPA (25 mL) and after 15 min methyl cyanoformate(45.0 g, 0.53 mol) in THF (20 mL) and the reaction warmed to roomtemperature and stirred for 3 hr. The reaction mixture was quenched with2N HCl (50 mL). The layers were separated and the aqueous phaseextracted with Et₂ O (1×500 mL). The combined organic extracts werewashed with saturated NH₄ Cl solution (3×50 mL), water (2×50 mL), brine(1×50 mL) and dried (Na₂ SO₄). Removal of the solvent in vacuo andpurification by Kugelrohr distillation afforded 34.0 g (99%) of methyl2,2-dimethyl cyclohexane-6-one carboxylate, bp 80°-84° C./0.6 mm.

The cyclohexanone was converted to4,4-dimethyl-4,5,6,7-tetrahydro-2-saccharinylmethyl2,6-dichlorobenzoate, mp 121°-123° C., following the procedure describedabove for Example 9D.

EXAMPLE11

Following the procedure of preparation 18A, 5 g of2-bromo-N,N-dimethylaniline was converted to 3.5 g ofN,N-diethyl-2-dimethylaminobenzamide. The amide was reacted by themethod of preparation 18B to provide 65 mg of 4-dimethylaminosaccharin,mp 228°-229° from ether-hexane. A mixture of 11.1 g of2,6-dichlorobenzoyl chloride, 1.9 g of paraformaldehyde and 0.1 g offused zinc chloride were heated at 100° for 2 hr and then vacuumdistilled to yield 3.5 g of chloromethyl 2,6-dichlorobenzoate collectedabove 145 ° at aspirator pressure which solidified on cooling, mp70°-72°. To a solution of 4-dimethylaminosaccharin and 0.1 mL ofdiisopropylethylamine in 1 mL of dry acetonitrile was added 100 mg ofchloromethyl 2,6-dichlorobenzoate. The mixture was stirred at roomtemperature for 48 hrs and then at 50° for 24 hours, when tlc (MDC)showed complete reaction. The mixture was poured into EtOAc andextracted with saturated NaHCO₃ solution. The organic layer was driedand the solvent removed at reduced pressure. Chromatography in MDCyielded 15 mg of 4-dimethylamino-2-saccharinylmethyl2,6-dichlorobenzoate.

BIOLOGICAL TEST RESULTS

Measurement of the inhibition constant, K_(i), of a HLE-inhibitorcomplex has been described for "truly reversible inhibition constants"usually concerning competitive inhibitors. [Cha, Biochem. Pharmacol.,24, 2177-2185 (1975)]. The compounds of the present invention, however,do not form truly reversible inhibitor complexes but are consumed by theenzyme to some extent. Thus, instead of measuring a K_(i), a K_(i) * iscalculated which is defined as the ratio of the k_(off) /k_(on), therate of reactivation of the enzyme to the rate of inactivation of theenzyme. The values of k_(off) and k_(on) are measured and K_(i) * isthen calculated.

The rate of inactivation, k_(on), of enzymatic activity was determinedfor the compounds tested by measuring the enzyme activity of an aliquotof the respective enzyme as a function of time after addition of thetest compound. By plotting the log of the enzyme activity against time,an observed rate of inactivation, k_(obs), is obtained which can berepresented as k_(obs) =1n2/t_(1/2) where t_(1/2) is the time requiredfor the enzyme activity to drop by 50%. The rate of inactivation is thenequal to ##EQU1## where [I] is the concentration of the inhibitingcompound.

The reactivation constant, k_(off), is similarly determined, and theinhibition constant, K_(i) *, is then calculated as

    K.sub.i *=k.sub.off /k.sub.on

The values obtained for k_(on) and K_(i) * for specific substitutedsaccharin derivatives are shown in TABLE 4, the compounds beingidentified by the Example numbers above where their preparations aredescribed.

                  TABLE 4                                                         ______________________________________                                                       k.sub.on × 10.sup.-3                                     Example        M.sup.-1 sec.sup.-1                                                                     K*.sub.i (nM)                                        ______________________________________                                         1A            375       0.08                                                  1B            522       0.023                                                 1C            28.9      0.40                                                  1D            6.3       8                                                     1E            3.1       18                                                    1F            14        3                                                     1G            3.7       18                                                    1H            9.3       8.5                                                   1I            46.0      0.48                                                  1J            670       0.03                                                  1K            250       0.09                                                  1L            77        0.30                                                  1M            92        0.25                                                  1N            3.4       31                                                    1-O           38        2                                                     1P            700       0.17                                                  1Q            900       0.03                                                  1R            460       1.0                                                   1S            30        2.0                                                   1T            15.3      4.0                                                   1U            2000      0.01                                                  1V            3000      0.007                                                 1W            2000      0.01                                                  1X            46        0.5                                                   1Y            192       0.12                                                  1Z            380       0.06                                                  1AA           2300      0.01                                                  1AB           1438      0.016                                                 1AC           920       0.025                                                 1AD           2875      0.008                                                 1AE           2556      0.009                                                 1AF           2300      0.01                                                  1AG           2300      0.01                                                  1AH           940       0.06                                                  1AI           24.5      2.7                                                   1AJ           10        8                                                     1AK           16        4                                                     1AM           45        2.1                                                   1AN           1.5       37.3                                                  1AO           23        1.0                                                   1AP           1100      0.011                                                 1AQ           923       0.013                                                 1AR           857       0.014                                                 1AS           769       0.013                                                 1AT           714       0.014                                                 1AU           333       0.030                                                 1AV           435       0.023                                                 1AX           --        0.033                                                 1AY           22.3      0.900                                                 1AZ           21.5      1.100                                                 1BA           --        0.078                                                 1BB           100       0.350                                                 1BC           1000      0.030                                                 1BD           --        0.070                                                 1BE           156       0.064                                                 1BF           5.4       2.000                                                 1BG           354       0.043                                                 1BH           15        0.600                                                 1BI           307       0.029                                                 1BJ           474       0.029                                                 1BK           129       0.088                                                 1BL           233       0.043                                                 1BM           125       0.080                                                 1BN           400       0.025                                                 1BO           200       0.050                                                 1BP           28.6      0.350                                                 1BQ           147       0.068                                                 1BR           175       0.057                                                 1BS           277       0.036                                                 1BT           --        --                                                    1BU           --        --                                                    1BW           51.3      0.200                                                 1BX           6.2       26.000                                                1BY           920       0.025                                                 1BZ           33        0.300                                                 2A            575       0.04                                                  2B            1150      0.02                                                  2C            --        --                                                    2D            1500      0.008                                                 3             2300      0.01                                                  3B            1091      0.011                                                 5A            200.00    0.050                                                 5B            281       0.057                                                 5C            583       0.030                                                 5D            333       0.030                                                 5E            880.5     0.017                                                 5F            --        0.027                                                 5G            --        0.054                                                  5J           --        0.200                                                 5K            12.3      2.200                                                 5L            0.70      30.000                                                6             583       0.016                                                 7A            320       0.080                                                 7B            331       0.056                                                 8             --        0.600                                                 9A            3.3       18.000                                                9B            36        1.000                                                 9C            83        0.700                                                 9D            10        1.000                                                 9E            13.3      2.000                                                10             18.5      1.000                                                11             35        0.200                                                ______________________________________                                    

We claim: 1.2-(2,6-Dichlorobenzoyloxymethyl)-4,5,6,7-tetrahydro-4,7-methano-1,2-benzisothiazol-3(2H)-one1,1-dioxide.